Diazepinones inhibitors of phosphodiesterase-iv

 

(57) Abstract:

The use in medicine of the described derivative diazepinone General formula I, where R and A are specified in the claims values, their racemic forms, their isomeric configuration defined by the carbon in position 3 diazepinone-4-about the kernel, and their pharmacologically acceptable salts, are inhibitors of phosphodiesterase-IV, pharmaceutical compositions on their basis, have increased in relation to the inhibition of phosphodiesterase IV activity. 3 S. and 8 C. p. F.-ly, 1 PL.

The invention relates to new, containing diazepambuy group of compounds with biological activity, and more particularly to a derivative of diazepinone, their racemic forms, their isomeric configurations defined by the carbon in position 3 diazepinone-4-about the kernel and their pharmacologically acceptable salts, intermediate compounds and pharmaceutical compositions inhibiting phosphodiesterase IV activity.

Known derivatives benzodiazepinea that exhibit properties antagonists cholecystokin (see application EP N 0340064 A1, class C 07 D 487/06, A 61 K 31/55, publ. 02.11.1989 year).

In addition, the known derivatives of PI is ith a phosphodiesterase IV activity (see application EP N 0463756 A1, class C 07 D 487/04 A 61 K 31/635, publ. 02.01.1995 year).

Object of the invention is the expansion of the range containing diazepambuy group of compounds with inhibiting phosphodiesterase IV activity.

The problem is solved proposed derivatives diazepinone General formula (I)

< / BR>
in which R is hydrogen, lower alkyl or lower alkoxyl;

A is phenyl, thienyl, 4-7-membered heterophilically the residue containing 1-4 nitrogen atom, unsaturated condensed heterocyclic residue with 1 to 5 nitrogen atoms, unsubstituted or substituted by 1-3 groups selected from the group comprising halogen, lower alkyl, lower halogenated, lower alkoxy, acetoxy, amino, tert.-butoxycarbonylamino, cycloalkylcarbonyl and ndimethylacetamide,

provided that when R is hydrogen, then:

I) A does not imply 2-indolinyl radical;

II) for racemic forms does not mean A phenyl radical, substituted with halogen; the halogen and amino; halogenoalkanes group; or 1-3 CNS groups

their racemic forms, their isomeric configurations defined by the carbon in position 3 diazepino-indol-4-about the kernel and pharmacology (I) includes compounds in which absolute configuration of the carbon atom in the-position to the carbonyl diazepinones cycle is (R)-configuration.

The second group derived diazepinone the above formula (I) include compounds in which A denotes a phenyl, pyridyl, thienyl, pyrimidyl, indolyl, hinely, ethanolic, pyrazolo-triazinyl, imidazo-pyridyl, imidazo pirimidil, unsubstituted or substituted by 1-3 groups selected from the group comprising halogen, lower alkyl, lower halogenated, lower alkoxy, acetoxy, amino, tert.-butoxycarbonylamino, cycloalkylcarbonyl and ndimethylacetamide.

The third group derived diazepinone the above formula (I) include compounds in which R signifies lower alkyl or lower alkoxyl.

In the fourth group derived diazepinone the above formula (I) include compounds in which R is methyl or methoxy group.

Particularly preferred derivatives of diazepinone formula (I) selected from the group including

a) (3R)-N-(4-oxo-1-phenyl-3,4,6,7-tetrahydro-[1,4] diazepino-[6,7,1-hi] indol-3-yl)isonicotinamide;

b) (4-oxo-1-phenyl-3,4,6,7-tetrahydro-[1,4] diazepino[6,7,1-hi]indol-3 - yl)amide(3R)-isoquinoline-3-carbon is] [1,2,4] -triazine-3-carboxylic acid;

g) (9-methyl-4-oxo-1-phenyl-3,4,6,7-tetrahydro-[1,4] diazepino[6,7,1-hi] indol-3-yl)amide(3R)-isoquinoline-3-carboxylic acid;

d) (3R)-4-chloro-N-(9-methoxy-4-oxo-1-phenyl-3,4,6,7-tetrahydro-[1,4] diazepino[6,7,1-hi]indol-3-yl)benzamide;

(e) (9-methoxy-4-oxo-1-phenyl-3,4,6,7-tetrahydro-[1,4]diazepino[6,7,1-hi] indol-3-yl)amide(3R)-quinoline-3-carboxylic acid;

W) (9-methoxy-4-oxo-1-phenyl-3,4,6,7-tetrahydro-[1,4]diazepino [6,7,1-hi]indol-3-yl)amide(3R)-quinoline-6-carboxylic acid;

C) (3R)-3-chloro-4-methoxy-N-(4-oxo-1-phenyl-3,4,6,7-tetrahydro-[1,4] diazepino[6,7,1-hi]indol-3-yl)benzamide;

and) (3R)-4-amino-3,5-dichloro-N-(4-oxo-1-phenyl-3,4,6,7-tetrahydro- [1,4] diazepino[6,7,1-hi]indol-3-yl)benzamide;

K) (3R)-5,6-dichloro-N-(4-oxo-1-phenyl-3,4,6,7-tetrahydro-[1,4] diazepino [6,7,1-hi]indol-3-yl)nicotinamide;

l) (3R)-2-methoxy-N-(9-methyl-4-oxo-1-phenyl-3,4,6,7-tetrahydro-[1,4] diazepino[6,7,1-hi]indol-3-yl)benzamide;

m) (3R)-N-(9-methyl-4-oxo-1-phenyl-3,4,6,7-tetrahydro-[1,4] -diazepino [6,7,1-hi]indol-3-yl)isonicotinamide;

n) (9-methyl-4-oxo-1-phenyl-3,4,6,7-tetrahydro-[1,4] diazepino[6,7,1-hi] indol-3-yl)amide(3R)-4,7-dimethyl-pyrazole-[5,1-C] [1,2,4]triazine-3 - carboxylic acid.

An additional object of the invention is a pharmaceutical composition inhibiting phosphodiesterase IV activity, which in addition to tarmac the Ia)

< / BR>
in which R1is hydrogen, lower alkyl or lower alkoxyl:

A1- phenyl, thienyl, 4-7-membered heterophilically the residue containing 1-4 nitrogen atom, unsaturated condensed heterocyclic residue with 1 to 5 nitrogen atoms, unsubstituted or substituted by 1-3 groups selected from the group comprising halogen, lower alkyl, lower halogenated, lower alkoxy, acetoxy, amino, tert. -butoxycarbonylamino, cycloalkylcarbonyl and ndimethylacetamide, its racemic form, or isomeric configuration defined by the carbon in position 3 diazepino-indol-4-about the kernel, or a pharmacologically acceptable salt.

As the preferred active substance of the proposed pharmaceutical composition comprises the compound of the above formula (I) indicated above as preferred.

By "pharmacologically acceptable salts" of the compounds of formulas (I) and (Ia) refers to salts with acids or bases.

As acids suitable non-toxic inorganic or organic acids, such as, for example, Hydrobromic, hydrochloric, sulfuric, sulfamic, phosphoric, nitric, acetic, propionic, succinic, glycolic, stearine the phenylacetic, glutamic, benzoic, salicylic, sulfonylurea, acetoxybenzoic, fumaric, toluensulfonate, econsultancy, oxalic acid, setinova and other acids. Suitable various salts of Quaternary ammonium derivatives of formula (I).

As grounds suitable inorganic or organic non-toxic bases, such as, for example, hydroxides of alkali and alkaline earth metals (lithium, sodium, potassium, magnesium and calcium), amides (dibenziletilendiaminom, trimethylamine, piperidine, pyrrolidine, benzylamine and others) or Quaternary ammonium hydroxides, as Tetramethylammonium-hydroxide.

Derivatives diazepinone the above formulas (I) and (Ia) are obtained by the known methods, for example, the fact that racemic or optically active amine of formula (II)

< / BR>
where R has the above meaning,

subjected to interaction with the carboxylic acid derivative of the formula (III)

< / BR>
where A has the above meaning and Z means a halogen, asiagraph, imidazol-1-ilen group, a group-O-CO-Z1, Z1< / BR>
maybe in addition to A spatial difficult alkyl radical of 3-6 carbon atoms; in addition, Z1can mean the group O-Z2where Z2

This method can be carried out in three variants a, B, C, using the parent compound (IIIA), (IIIB), and (V), respectively:

< / BR>
Options a, B and C can be carried out as follows.

Option a:

The compound of formula (II) is dissolved in 5-50 volume anhydrous organic solvent, e.g. a chlorinated hydrocarbon, such as dichloromethane or chloroform; a linear or cyclic simple ether, such as 1,2-dimethoxyethane, tetrahydrofuran or dioxane; polar aprotic solvent, such as pyridine, dimethyl sulfoxide or dimethylformamide, or any other solvent suitable for the implementation of the condensation reaction, or in an appropriate mixture of two or more of these solvents, and the resulting solution add 1-2 equivalent galodamadruga acid of the formula A-CO-X in which X represents halogen, preferably chlorine, and A have the above meaning.

Then add the same equimolar amount of an inorganic or organic base, preferably triethylamine, and stirred at a temperature of from -20oC to the boiling temperature of the reaction medium during the time from 30 minutes to 24 hours. The reaction mixture VMS solution of inorganic acid, a saturated solution of sodium bicarbonate and then with water.

After evaporation of the solvent the product is usually purified by flash chromatography on a column of silica using the method developed by Still and others D. Org. Chem., 43, 2923 (1978).

Option B:

Stage 1:

The compound of formula A-COOH, in which A has the abovementioned meaning, are dissolved in 5-50 volume of an organic solvent such as the solvents described for method A. the resulting solution add three equivalent compounds of formula Z2-OH, where Z2has the above value, and the preferred groups Z2are p-nitrophenyl, 2,4-dinitrophenyl and, in particular, pentafluorophenyl, in the presence of a dehydrating agent, such as carbodiimide, and possibly pyridinium salt. Reaction conditions similar to those of option A. After evaporation of the solvent the product, depending on its purity determined by means of thin layer chromatography, and purified by flash chromatography or used as is, in the reaction stage 2.

Stage 2:

Obtained in the previous phase ester is added to one equivalent of the compound of formula (II), dissolved in anhydrous atilim flash chromatography.

Option:

To the compound of formula (II), dissolved in 5-50 volume one of the above in the case of A solvent, is added in small excess of the acid of formula A-COOH, in which A has the abovementioned meaning, in the presence of one equivalent of a condensing agent such as N,N'-disubstituted of carbodiimide, N,N'-carbonyldiimidazole, or as the preferred O- [(etoxycarbonyl)cyanomethylene]-N,N,N',N'-tetramethyluronium - tetrafluoroborate or bromo-Tris(pyrrolidinone)hexaflurophosphate, and two equivalents of a tertiary amine. Reaction conditions similar to those of option A.

The mixture is extracted successively with dilute solution of an inorganic acid, a saturated solution of sodium bicarbonate and water. After evaporation of the solvent the product was then purified by flash chromatography.

An additional object of the invention are derivatives of diazepinone the above formula (II) in which R denotes methyl or methoxy group, which are intermediate compounds for obtaining derivatives diazepinone the above formula (I) in which R is methyl or methoxy.

Racemic and/or enantiomeric amines of the above borbonia of diazepinone formula (IV)

< / BR>
using hydroxylamine derivative or chloramines; or, in two stages, by reacting the compounds of formula (IV) with eximious reagent to obtain the oxime of formula (V)

< / BR>
the second stage consists in the catalytic reduction of the oxime with hydrogen in the presence of a catalyst recovery or by reaction with zinc in the presence of acetic acid or tin chloride (II). Here at the end of the scheme illustrates the synthesis of compounds of formula (II).

The indole of the formula (IX) is reduced to the corresponding indoline formula (VIII), which condense with benzonitrile formula (VII) in the presence of a Lewis acid to obtain, after hydrolysis, benzophenone of the formula (VI).

The product of formula (IV) of the product of formula (VI) in the presence of ethylglycine carried out in pyridine according to the method described Hester J. B. et Al., J. Med. Chem., 13, 827-835 (1970).

To obtain optically active compounds of the formula (II) can act as follows:

- condensing racemic compound of the formula (II) with a derivative of amino acids in the formula D or L, in which the amino function is protected by easily removable group, preferably tert.-butyloxycarbonyl groupdrive triperoxonane acid, and the product be divided into its diastereoisomer using chromatography; get two isomer amine is condensed with an amino acid. By decomposition of Atmano again receive two enantiomers of an amine of the formula (II); or:

- dissolving the racemic compound of the formula (II) in a solution of an optically active acid, such as, for example, in the enantiomer almond, dibenzoyltartaric, di-p-toluylene, camphor-sulfonic, p-nitrobenzylamine or tartaric acids, with the aim of obtaining two diastereoisomeric salts, then, due to differences in solubility, to selectively crystallize one of them from the appropriate solvent.

Obtaining derivatives of diazepinone the above formulas (I) and (Ia) is illustrated by the following examples, in which the purity, identity and physico-chemical characteristics of the intermediate and target products is determined as follows:

the purity determined by thin-layer chromatography on silica gel (Merck 60-F254) and the observed Rf correlated to the solvent used for elution, which is most often identical to that used for preparative chromatographic purification of compounds. These solvents are used in the AI 97:3 by volume;

S. A2: a mixture of dichloromethane with acetone in the ratio 96:4 by volume;

S. A3: a mixture of dichloromethane with acetone in a ratio of 95:5 by volume;

S. A4: a mixture of dichloromethane with acetone in the ratio of 90:10 by volume;

S. A5: a mixture of dichloromethane with acetone in a ratio of 88:12 by volume;

S. A6: a mixture of dichloromethane with acetone in the ratio of 85:15 by volume;

S. A7: a mixture of dichloromethane with ethyl acetate in the ratio of 98:2 by volume;

S. A8: a mixture of dichloromethane with methanol in the ratio of 98:2 by volume;

S. A9: a mixture of dichloromethane with methanol in the ratio of 97:3 by volume;

S. A10: a mixture of dichloromethane with methanol in the ratio of 95:5 by volume;

S. B: ethyl acetate;

S. B1: a mixture of ethyl acetate with cyclohexane in the ratio of 70:30 by volume;

S. B2: a mixture of ethyl acetate with cyclohexane in the ratio of 60:40 by volume;

S. B3; a mixture of ethyl acetate with methanol in the ratio of 97:3 by volume;

S. B4: a mixture of ethyl acetate with methanol in the ratio of 95:5 by volume;

- identity elemental formulas of the compounds obtained with the elemental formula of the target structures is confirmed by analyzing the basic elements. The results are stated in accordance with the proposed structure, taking into consideration the possible solvate or hydrate;

- identity received Prem their infrared spectra.

Spectra1NMR shoot at 400 MHz on the device mark Brucker, and compounds dissolved in deuterium chloroform with three-methylsilanol as an internal standard. Indicate the nature of the signals, chem. the shift in M. D. (millionths), the number of protons to which they belong, and their ion-exchange capacity with D2O.

Infrared spectra were recorded using tablets of potassium bromide spectrometer, Shimada IR-435;

as physico-chemical properties are: melting point compounds, determined according to the method in the capillary, and the corresponding values of which are reported without amendment; the rotational ability of the compounds determined at room temperature, close to the 20oC, on the device Polartronic in a cell with a length of 10 cm, and the determination results which in some cases allow us to estimate the optical purity by calculating the excess of one enantiomer (E. E.). To standardize the chemical nomenclature of the products obtained is a such defined using the software "Autonom", version 1.0 Beilstein Institut ed. Springler), which creates a systematic nomenclature of the compounds according to IUPAC rules. Also for simplicity ol 'ptx2">

Intermediate compounds of formula (II)

The intermediate compound (1.: (3RS)-3-Amino-1-phenyl-6,7 - dihydro-3H-[1,4]diazepino[6,7,1-hi]indol-4-one (II-R,S).

Connection receive according to the method described in example 1, stage a) and (b), of European application N 0340064.

The intermediate compound (1.b): (3R)-3-Amino-1-phenyl-6,7 - dihydro-3H-[1,4]-diazepino[6,7,1-hi]indol-4-one (II-R).

The connection is described in example 5, stage a), b), C), (d), (h), the experimental part of the aforementioned application EP N 0340064 A1. However, the preferred alternative, which consists in the separation by fractional crystallization of intermediate racemic compounds (1.a) due to the formation and separation of diastereoisomers with N-acetyl-L-phenyl-alanine:

- 74,0 g (267 mmol) of (3R,S)-3-Amino-1-phenyl-6,7-dihydro-3H- [1,4]diazepino[6,7,1-hi] indol-4-it (intermediate compound (1.a)) is dissolved in 210 ml of boiling n-propanol. At the same time of 44.1 g (267 mmol) of N-acetyl-L-phenyl-alanine are dissolved in 140 ml of boiling n-propanol. Both solution are mixed, allowed to cool, make a seed crystal in the form of several crystals. After incubation for three days, the crystals are filtered and dried. The mass is 50.0 g (that is, ie = 77%). Product precrystallization is lisali is evaporated, the residue is treated with boiling ethyl acetate. After crystallization, filtration and drying receive 35,0 g of crystals (that is, ie = 50%), which, after two consecutive kristallizatsii from boiling ethyl acetate, allow to obtain 17.0 g (that is, ie = 97%) of product. United two batches of crystals give 56,0 g (yield = 95%) salt (3R)-enantiomer amine with N-acetyl-L-phenyl-alanine. So pl. = 171oC. []D= +132o(C = 1, methanol).

- 42,4 g (96 mmol) of salt (3R)-amine intensively stirred in the presence of 500 ml of ethyl acetate and 500 ml of 1 n sodium hydroxide solution. After dissolving an ethyl acetate phase is separated, washed with saturated sodium chloride water, and then dehydration and evaporated. Obtain 25.4 g of the intermediate amine (1.b). Yield = 95%. So pl. = 79oC. []D= +172o(C = 1, dichloromethane).

1NMR, (M. D.): 3,05-3,5 (m, 2H), 3,3 (ush.s, 2H, exchangeable); 3,9-4,0 (m, 1H); 4,6-4,7 (m, 1H), 7,05 and 7.6 (m, 9H). IR-spectrum: 3350, 1670, 1600, 1560, 1420, 1380, 1340, 1290, 1240, 760, 730, 690 cm1.

The intermediate compound (2.(a): (3R,S)-3-Amino-9-methyl-1 - phenyl-6,7-dihydro-3H-[1,4]diazepino[6,7,1-hi]indol-4-one

(II-R,S; R = CH3)

- Stage 1: 5-Methyl-indolin

To a solution of 20.0 g (152 mmol) of 5-methyl-indole in 300 ml of glacial acetic acid at a temperature below 20oC Macchi exercise within three hours, and it is accompanied by a slight evolution of hydrogen. Stirred for 12 hours at a temperature below the 20oC, then add 300 ml of water and pH of the reaction medium is brought to 10-12 by adding 500 ml of 30% sodium hydroxide solution. The mixture is extracted twice with dichloromethane, then the organic phase is washed with 100 ml of water. Is evaporated, the residue is purified by flash chromatography on a column of silica, and used an eluting agent is a mixture of increasing polarity of methanol in dichloromethane. Gain of 15.3 g (yield = 75%) of colorless oil, which when stored painted in brown color (nitrogen atmosphere and the absence of light). TLC (thin layer chromatography): p. A8; 0,39.

1NMR, (M. D. ): 2,2 (s, 3H); 2.95 and (t, 2H); 3,4 (m, 3H, 1 exchange); and 6.5 (d, 1H); to 6.8 (d, 1H); to 6.95 (s, 1H).

- Stage 2: 7-Benzoyl-5-methyl-indolin

13,70 g (103 mmol) of 5-Methyl-indoline dissolved in 360 ml of 1,2-dichloroethane. At temperatures below 5oC was added dropwise 13,24 g (113 mmol) of trichloride boron in the form of a 1M solution in dichloromethane, 20,36 g (197 mmol) of benzonitrile, then 13,73 g (103 mmol) of anhydrous trichloride aluminum. The mixture is boiled for 16 hours under reflux (temperature of the mass is agrimonia for 20 minutes at 80oC. Leave to cool until the 20oC and the extraction is carried out with dichloromethane. The aqueous phase is re-extracted with 100 ml dichloromethane. The combined organic phases are washed with sodium hydroxide solution, then concentrated solution of sodium chloride and dried over sodium sulfate. After filtration and evaporation receive 22,10 g solid yellow color. Yield = 91%. So pl. = 84oC. the Appropriate analysis for CHNO.

TLC: S. A, 0,46.

1NMR (M. D.): 2,2 (s, 3H); 3,05 (t, 2H); 3.75 to (t, 2H); 6,9 (ush.s, 1H exchangeable); 7,05 (ush.s, 2H); 7.5 (m, 3H); the 7.65 (m, 2H).

- Stage 3: 9-Methyl-1-phenyl-6,7-dihydro-3H-[1,4]diazepino[6,7,1-hi] indol-4-one In 140 ml of pyridine enter 21,0 g (88 mmol) of 7-benzoyl-5-methyl-indoline, then 43,2 g (31 mmol) ethylglycine - hydrochloride. Heated with stirring at a temperature of 110-115oC, constantly fending off the formed light fractions. After 12 hours, cool and add 150 ml of 2.5% aqueous solution of sodium carbonate in water and 150 ml of dichloromethane. The aqueous phase is separated, extracted with 150 ml of dichloromethane. The organic phases are combined and washed with water. The solvent is evaporated, then the residue purified by flash chromatography on a column of silica, and used algirus the CSOs color. Yield = 80%. So pl. = 132oC.

TLC: S. B; 0,70.

1NMR, (M. D.): 2,3 (s, 3H); 3.15 in (t, 2H); 4.25 in (t, 2H); 4,3 (t, 2H): 7,0 (s, 1H); to 7.25 (s, 1H); was 7.45 (m, 3H); at 7.55 (m, 2H).

Stage 4: 3 Hydroxyimino-9-methyl-1-phenyl-6,7-dihydro-3H- [1,4]diazepino-[6,7,1-hi]indol-4-one

21,0 g (76 mmol) videolounge product is dissolved in a mixture of 84 ml of tetrahydrofuran and 168 ml of toluene. Cool and when the temperature is below 0oC type of 21.3 g (190 mmol) of tert.-the butyl potassium. Adding exothermic reaction occurs and the solution turns black. After stirring for 20 minutes for 10 minutes add about a 9.35 g (80 mmol) of isoamylamine. Stirred for 10 minutes at a temperature below 0oC, then add to 31.2 ml of glacial acetic acid and 300 ml of water. The insoluble part is filtered off and add 200 ml of dichloromethane. Decanted and the aqueous phase is washed with 200 ml of dichloromethane. The organic phases are combined and washed with 200 ml of water. After evaporation of the solvent the residue is treated with 40 ml of methanol. Vegascasinoonline the product is filtered, washed with 20 ml of chilled methanol, then dried. Get to 15.06 g of solid yellow. Yield = 65%. So pl. = 247oC.


of 1.32 g of 5% ruthenium-on-coal added to a solution of 4.4 g (14.4 mmol) obtained in the previous stage of the product in 150 ml of methanol. Hydronaut at a pressure of 8 bar at 80oC for 6 hours, then filtered and the catalyst washed. After evaporation the residue is purified by flash chromatography on a column of silica, and used an eluting agent is a mixture of ethyl acetate, progressively enriched with methanol. Get 2,87 g purified amine in the form of a solid yellow-beige color. Yield = 68%, So pl. = 116oC.

TLC: S. B4; 0,14.

1NMR, (M. D.): 2,3 (s, 3H): 2,4 (ush.s, 2H, exchangeable); 3,1 (m, 1H); 3,3 (m, 1H); 3,95 (m, 1H); with 4.65 (m, 1H); 7-7,6 (m, 8H).

The intermediate compound (2.b): (3R)-3-Amino-9-methyl-1-phenyl - 6,7-dihydro-3H-[1,4]diazepino[6,7,1-PZ-]indole-4-one (II-R; R = CH3) 19,95 g (68 mmol) of (R,S)-amine of the formula (2.a) are dissolved in 200 ml of acetonitrile while boiling under reflux. At the same time, 26,45 g (68 mmol) of di-p-toluoyl-tartaric acid are dissolved in 260 ml of acetonitrile while boiling under reflux. Hot solutions are mixed, then incubated for 24 hours at room temperature. The white crystals are filtered and washed with 100 ml of chilled acetonitrile and the obtained product to the chromatographic column type Pirckle when elution with a mixture of isopropanol with cyclohexane in the ratio of 50: 50 by volume. The filtered crystals 20.6 g (that is, ie = 45%) is recrystallized three times consecutively from acetonitrile to obtain the pure product (that is, ie = 98%). Obtain 12.0 g of product. So pl. = 233oC.

[]D+177o(C = 1, methanol).

Videolooking salt is suspended in 100 ml of ethyl acetate. With vigorous stirring, a saturated solution of sodium bicarbonate. After a few minutes, the aqueous phase is removed. The organic phase is washed with water, dried, then the solvent is evaporated under cold nitrogen atmosphere. Get cleared basis. So pl. = 68oC.

[]D= +207o(C = 1, dichloromethane).

The intermediate compound (3. (a): (3R,S)-3-Amino-9-meth-oxy-1 - phenyl-6,7-dihydro-3H-[1,4]diazepino[6,7,1-hi]indol-4-one (II-R, S; R= CH3O)

The compound is obtained from 5-methoxy-indole in 5 stages according to the procedure described for intermediate connection (2.a):

Stage 1: 5-Methoxy-indolin

Yield = 83%. Light yellow liquid, which turns on the light.

TLC: S. B2; 0,38.

1NMR, (M. D.): 3,0 (t, 2H); 3,41 (s, 1H exchangeable); 3,5 (t, 2H); 3,7 (s, 3H); and 6.6 (s, 2H); at 6.8(s, 1H).

Stage 2: 7-Benzoyl-5-methoxy-indolin

Yield = 38%. Solid, oranges which 1H exchangeable); 6,95 (ush.s, 1H); 7,4-of 7.55 (m, 3H); the 7.65 (m, 2H).

Stage 3: 9-Methoxy-1-phenyl-6,7-dihydro-3H-[1,4]diazepino [6,7,1-hi]indol-4-one

Yield = 82%: Resin brown.

TLC: S. A6; 0,73.

1NMR, (M. D.): 3,1 (t, 2H); 3,7 (s, 3H): 4,3 (t, 2H); 3.9 to (s, 2H): 6,6 (s, 1H); 7,0 (s, 1H); 7.3 to 7.5 (m, 3H); to 7.6 (d, 2H).

Stage 4: 3 Hydroxyimino-9-methoxy-1-phenyl-6,7-dihydro-3H- [1,4]diazepino[6,7,1-hi]indol-4-one

Yield = 53%. Solid yellow-orange color. So pl.= 205oC.

TCX: S. A5,0,17.

1NMR, (M. D.): 3,2 (t, 2H); 3,7 (s, 3H); 4,4 (t, 2H); 6,7 (t, 2H); and 7.1 (s, 1H); 7,4-7,6 (m, 3H); 7,8 (d, 2H); and 8.6 (s, 1H).

Stage 5: (3R,S)-3-Amino-9-methoxy-1-phenyl-6,7-dihydro-3H- [1,4]diazepino-[6,7,1-hi]indol-4-one.

Yield = 67%. Solid yellow-beige color. So pl. = 84oC.

TCX: S. B3; 0,24.

1NMR, (M. D.): 3,2 (t, 2H); 3,7 (s, 3H); 4,4 (t, 2H); 5,3 (s, 1H); 6,7 (s, 1H); and 7.1 (s, 1H): 7,4-7,8 (m, 5H); 2,1 and 8.5 (ush.s, 2H, exchangeable).

The intermediate compound (3.6): (3R)-3-Amino-9-methoxy-1 - phenyl-6,7-dihydro-3H-[1,4]diazepino[6,7,1-hi]indol-4-one

(II-R; R=CH3O).

10.0 g (32,3 mmol) of (R,S)-amine of the formula (3.a) are dissolved in 100 ml of acetonitrile while boiling under reflux. At the same time 12,47 g (32,3 mmol) di-p-toluoyl-tartaric acid are dissolved in 100 ml of acetonitrile boiling is about room temperature. After standing over night the white crystals are filtered and washed them with 100 ml of cold acetonitrile, and then dried. These crystals (E. E. = 37%) is recrystallized 2 times consecutively from acetonitrile to obtain the pure product (E. E. 99,5%). After this cleaning exercise chromatography using columns with optically active stationary phase C18type Pirckle, elwira a mixture of ISO-propanol with n-hexane in the ratio of 50:50. Get 9,9 r product. Yield = 44%. So pl. = 168oC.

to 9.9 g viseporodicnog salt is suspended in 100 ml of ethyl acetate. With vigorous stirring, a saturated solution of sodium bicarbonate, after a few minutes, remove the aqueous phase. The organic phase is washed with 50 ml of water, dried, then the solvent is evaporated under cold nitrogen atmosphere. Obtain 4.1 g of purified Foundation. Yield = 95%. So pl. = 84oC. []D= +23o(C = 1,1: dichloromethane).

Examples of preparing compounds of formula (I) according to the invention

As described above, the compounds of formula (I) according to the invention is produced by the interaction of 3-amino-1-phenyl-6,7 - dihydro-3H-[1,4]diazepino[6,7,1-hi] indol-4-ones, intermediates forms the Rami of the formula (IIIB) according to option B or with carboxylic acids of the formula (V) under option C. Listed below are the common methods of implementing these methods.

Option a:

Protected from moisture reactor, with stirring, 10.0 mmol amine intermediate of formula (II) is dissolved in 60 ml of anhydrous dichloromethane. At a temperature of about 20oC then add 10.0 mmol of galodamadruga acid of formula (IIIA), then added dropwise 10.0 mmol of triethylamine. The reaction proceeds under stirring and at room temperature between 15 and 20oC and the progress monitored using thin-layer chromatography. When the reaction is complete, add 120 ml of dichloromethane to the reaction mixture, the mixture is extracted successively with 60 ml of 1 n hydrochloric acid solution, 60 ml of a saturated solution of sodium bicarbonate and, finally, 60 ml of water. After drying the dichloromethane is evaporated under reduced pressure, the residue is purified by flash chromatography using a column with silica and eluting agent is a mixture of increasing polarity, formed, for example, acetone in dichloromethane. Fractions after elution containing, as defined, net connection, unite, then evaporated under reduced pressure. For cleaned of residual product define stromule A-COOH and 3.55 g (19,3 mmol) pentafluorophenol dissolved in 25 ml of dichloromethane. Then add 0,81 g (2.6 mmol) of p - dimethylaminopyridine-p-toluensulfonate and either of 22.4 mmol of dicyclohexylcarbodiimide for option "b", or of 22.4 mmol of N-(3 - dimethylaminopropyl)-N'-ethyl-carbodiimide for option "b b".

The mixture is stirred for 16 hours at room temperature of about 20oC, then the insoluble part is filtered off. The solvent is distilled off, the residue is purified by flash chromatography on a column of silica, using as the most frequently used eluting means the gradient of acetone in dichloromethane. The fractions containing pure compound according to TLC) are pooled, the solvent is evaporated, and after the analysis of the residual of the intermediate ester (IIIB), in the form of an amorphous foam used as is in the subsequent stage.

Stage 2: 10.0 mmol obtained in the previous stage complex pentafluorophenyl ester (IIIB) are added to 10.0 mmol amine intermediate of formula (II), dissolved in anhydrous ethyl acetate. After stirring for 16 hours at room temperature of about 20oC insoluble part is filtered off, the ethyl acetate is evaporated in vacuo, then the residue purified by the method of flash-chromatography on a column dioxide, PU glue is racchi, containing pure compound according to TLC) are pooled, the solvent evaporated and the residue purified identify and analyze.

Option:

Protected from moisture reactor, with stirring, 10.0 mmol amine intermediate of formula (II) is dissolved in a 50.0 ml of anhydrous dichloromethane. Then at room temperature for about 20oC add 11.0 mmol intermediate acid (III) of the formula A-COOH, then 10.0 mmol (3.28 g) "TOTU" (abbreviated o- [(etoxycarbonyl)cyanomethylene]-N,N,N',N'-Tetra-metilamoniu - tetrafluoroborate - producer company Fluka, standard notation 02580). The mixture is cooled to 0oC, then add 20.0 mmol (2.55 g) in N,N-diisopropylethylamine, and the mixture is stirred for 12 hours at room temperature, then extracted sequentially with 50 ml of 1 n hydrochloric acid, 50 ml of a saturated solution of sodium bicarbonate and finally with 50 ml water. The solvent is removed in vacuo, and the residue purified by the method of flash-chromatography on a column of silica, using most often used as the eluting means the gradient of methanol in dichloromethane. The fractions containing pure compound according to TLC) are pooled, the solvent evaporated, and the cleansing [6,7,1-hi] indol-3-yl)-amide(3R,S)-2-chloro-4-trifluoromethyl-pyrimidine-5 - carboxylic acid

[formula (I); A = 5-(2-chloro-4-trifluoromethyl-pyrimidyl)].

Connection receive under option A, based on the intermediate (1. a) and the acid chloride of 5-(2-chloro-4 - trifluoromethyl) pirimidil-carboxylic acid. Yield = 72%.

Solid white color. So pl. = 282oC (decomposition).

The analysis is consistent with C23H15ClF3N5O2.

TLC: S. A4:0,70.

1NMR (dimethylsulfoxide), (M. D.): of 2.9 to 3.6 (m, 2H); 3,7-4,2 (m, 1H); 4,4-of 4.75 (m, 1H); of 5.45 (d, 1H, becomes a singlet due to the exchange); a 7.1 to 7.8 (m, 8H); a 9.25 (s, 1H); 10,2 (d, 1H exchangeable);

IR-spectrum: 3200, 1670, 1560, 1540, 1520, 1430, 1345, 1210, 1140, 800, 735, 700 cm-1.

Example 1. B: M-(4-Oxo-1-phenyl-3,4,6,7-tetrahydro-[1,4] diazepino [6,7,1-hi] indol-3-yl)-amide(3R,S)-imidazo[1,2-a]pyridine-2-carboxylic acid [formula (I); A = 2 imidazo[1,2-a]pyridinyl].

The connection is obtained from the intermediate product (1.a), imidazo[1,2-a] pyridine-2-carboxylic acid according to the method based on the variant, which consists in carrying out the condensation in tetrahydrofuran (THF) in the presence of bromo - Tris(pyrrolidinone)hexaflurophosphate ("Rougher") and triethylamine. 4,50 g (16,23 mmol) of the intermediate amine (1.a) is dissolved in 150 ml of anhydrous THF. Add 3,20 g (with ice and add 9,13 g (to 18.6 mmol) "Rougher in 50 ml of THF. After stirring for 16 hours at room temperature, filtered, the insoluble portion, and the solvent is removed by distillation in vacuum. The residue (12.2 g) purified by chromatography on a column of silica, elwira with ethyl acetate containing 5% of acetone. The fractions containing the purified product according to TLC, are combined and the solvent is evaporated. Get a 5.1 g of pure product as an amorphous substance. Yield = 71%. So pl. = 260oC. the Analysis is consistent with C25H19FN5O2H2O.

TLC: S. A6; 0,27.

1NMR (M. D.): 2,80-3,55 (m, 2H), 3,70-4,10 (m, 1H), 4,30-of 4.75 (m, 1H); 5,50-of 5.68 (d, 1H, after the exchange becomes a singlet); 6,65-of 7.70 (m, 11H); 8,00-of 8.15 (m, 2H); cent to 8.85-of 8.95 (d, 1H exchangeable).

IR-spectrum: 3100, 1725, 1640, 1520, 1390, 1275, 1020, 820, 800, 750 cm-1.

Example 2.A: (3R)-2-Fluoro-N-(4-Oxo-1-phenyl-3,4,6,7-tetrahydro- [1,4]diazepino[6,7,1-hi]indol-3-yl)benzamide

[formula (I); A = 2-forfinal]

Connection receive under option a of the intermediate compound (1.6) and 2-tormentilla. Output = 50.5 per cent.

Amorphous solid. So pl. = 192oC. []D= +51o(C = 1, dichloromethane).

The analysis is consistent with C24H18FN3O2.

TLC: S. A3; 0,43.

1

IR-spectrum: 3300, 1640, 1490, 1430, 1380, 1340, 1230, 1160, 725, 690 cm-1.

Example 2. B: (3R)-3-Fluoro-N-(4-Oxo-1-phenyl-3,4,6,7-tetrahydro- [1,4]diazepino[6,7,1-hi]indol-3-yl)benzamide [formula (I)

[formula (I); A = 3-forfinal]

Connection receive under option a of the intermediate product (1.b) and 3 - tormentilla. Yield = 78%. Amorphous solid. So pl. = 244oC. []D= +48o(C = 1, dichloromethane). The analysis is consistent with C24H18FN3O20.5 H2O.

TLC: S. A3; 0,43.

1NMR, (M. D.): 3.15 in (m, 1H); to 3.35 (m, 1H); 4,00 (m, 1H); with 4.65 (m, 1H); ceiling of 5.60 (d, 1H); 7,10 - of 7.60 (m, 10H); the 7.65 7,80 (m, 2H); 8,00 (d, 1H exchangeable).

IR-spectrum: 3250, 1670, 1620, 1580, 1520, 1430, 1380, 1340, 1280, 1240, 1220, 1140, 790, 670 cm-1.

Example 2.In: (3R)-4-Fluoro-N-(4-Oxo-1-phenyl-3,4,6,7-tetrahydro- [1,4]diazepino[6,7,1-P1]indol-3-yl)benzamide

[formula (I); A = 4-forfinal]

Connection receive under option a of the intermediate product (1.b) and 4-tormentilla.

Output = 50.4 percent. Amorphous solid. So pl. = 228oC.

[]D= +48 (C = 1, dichloromethane). The analysis is consistent with C24H18FN3O20,25 H2O.

TLC: S. A3; 0,52.

1NMR, (M. D.): 3.15 in (m, 1H); to 3.35 (m, 1H); 3,95 (m, 1H); with 4.65 (m, 1H); ceiling of 5.60 (the 800, 760, 690, 660 cm-1.

Example 2. G: (3R)-2-Chloro-N-(4-oxo-1-phenyl-3,4,6,7-tetrahydro- [1,4]diazepino]6,7,1-hi]indol-3-ID)benzamide

[formula (I); A = 2-chlorophenyl]

Connection receive under option a of the intermediate product (1.b) and 2-chlorobenzylchloride. Yield = 66%. Amorphous solid. So pl. = 121oC. []D= +82o(C = 1, dichloromethane). The analysis is consistent with C24H18FN3O20,1 CH2Cl2.

TLC: S. A3; 0,57.

1NMR, (M. D.): 3.15 in (m, 1H); to 3.35 (m, 1H), 4.00 points (m, 1H); with 4.65 (m, 1H); ceiling of 5.60 (d, 1H), 7,10 (m, 1H); 7,20-of 7.60 (m, 10H); 7,80 (m, 1H); 8,00 (d, 1H exchangeable).

IR-spectrum: 3300, 1650, 1590, 1490, 1430, 1380, 1220, 1160, 1040, 750, 730, 690 cm-1.

Example 2. D: (3R)-3-Chloro-N-(4-oxo-1-phenyl-3,4,6,7-tetrahydro- [1,4]diazepino[6,7,1-hi]indol-3-yl)benzamide

[formula (I); A = 3-chlorophenyl]

Connection receive under option a of the intermediate product (1.b) and 3-chlorobenzylchloride. Yield = 85%. Solid white color. So pl. = 230oC (decomposition). []D= +34o(C = 1, dichloromethane). The analysis is consistent with C24H18ClN3O2.

TLC: S. A3; 0,49.

1H-NMR, (M. D. ): 3.15 in (m, 1H); to 3.35 (m, 1H); 4,00 (m, 1H); of 4.67 (m, 1H); the 5.65 (d, 1H, which becomes a singlet due to the exchange); to 7.15 (m, 1H); 7,25 (m, 1H); 7.3 to about 7.6 (m, P>-1
.

Example 2. E: (3R)-2-Iodine-N-(4-oxo-1-phenyl-3,4,6,7 - tetrahydro-[1,4]diazepino[6,7,1-hi]INDD-3-yl)benzamide

[formula (I), And = 2-itfeel]

Connection receive under option a of the intermediate product (1.b) and 2-identilied. Yield = 69%. Amorphous solid. So pl. = 123oC. []D= +81o(C = 1, dichloromethane). The analysis is consistent with C24H18IN3O2.

TLC: S. A3; 0,55.

1NMR, (M. D.): 3.15 in (m, 1H); 3.40 in (m, 1H); 4.0 a (m, 1H); of 4.67 (m, 1H), 5,65 (d, 1H, which becomes a singlet due to the exchange): for 7.12 (m, 2H): 7,25 (m, 1H): 7,3-7,5 (m, 5H); 7,58 (m, 2H): of 7.70 (m, 2H, of which 1H exchangeable); a 7.92 (d, 1H).

IR-spectrum: 3400, 3260, 1650, 1490, 1440, 1385, 1160, 725, 690 cm-1< / BR>
Example 2. W: (3R)-3-Chloro-4-fluoro-N-(4-oxo-1-phenyl-3,4,6,7-tetrahydro- [1,4]diazepino[6,7,1-hi]indol-3-yl)benzamide

[formula (I); A = 3-chloro-4-forfinal]

Connection receive under option b of the intermediate product (1.b) and 3-chloro-4-fluoro-benzoic acid. Yield = 97%. Amorphous solid. So pl. = 148oC. []D= +43o(C = 1, dichloromethane). The analysis is consistent with C24H17ClFN3O2.

TLC: S. A3; 0,70.

1NMR, (M. D.): 3.15 in (m, 1H); to 3.35 (m, 1H); 4,00 (m, 1H) and 4.65 (m, 1H); 5/60 (d, 1H); 7,10-of 7.60 (m, 9H, of which 1H exchangeable); a 7.85 (m, 1H); 8N-(4-oxo-1-phenyl-3,4,6,7 - tetrahydro-[1,4] diazepino[6,7,1-hi]indol-3-yl)benzamide

[formula (I); A = 3,4-dichlorophenyl]

Connection receive under option a of the intermediate product (1.b) and 3,4-dichlorobenzotrifluoride. Output = 85,4%. Amorphous solid. So pl. = 163oC. []D= +42o(C = 1, dichloromethane). The analysis is consistent with C24H17Cl2N3O2.

TLC: S. A3; 0,76.

1NMR, (M. D.): 3.15 in (m, 1H); to 3.35 (m, 1H); 4,00 (m, 1H); with 4.65 (m, 1H); ceiling of 5.60 (d, 1H); 7,10-of 7.60 (m, 9H, of which 1H exchangeable); a 7.85 (m, 1H); with 8.05 (m, 2H).

IR-spectrum: 3300, 3050, 1640, 1500, 1440, 1380, 1280, 1230, 1130, 1020, 750, 730, 690 cm-1.

Example 2: (3R)-2-Methyl-N-(4-oxo-1-phenyl-3,4,6,7 - tetrahydro-[1,4]diazepino[6,7,1-P1]indol-3-yl)benzamide

[formula (I); A = 2-were]

Connection receive under option a of the intermediate product (1.b) and 2-methylbenzylamine. Yield = 33%. Solid white color. So pl. = 154oC. []D= +78o(C = 1, dichloromethane). The analysis is consistent with C25H21N3O3.

TLC: S. A3; 0,34.

1NMR, (M. D.): 2,6 (s, 3H); 3.15 in (m, 1H); to 3.38 (m, 1H); of 3.48 (m, 1H); and 4.68 (m, 1H); to 5.66 (d, 1H, becomes a singlet due to the exchange): for 7.12 (m, 1H); 7,25 (m, 3H); 7.3 to 7.5 (m, 5H); 7,56 (m, 2H); to 7.68 (m, 2H, of which 1H exchangeable).

IR-spectrum: 3300, 3000, 1650, 1470, 1440, 1380, 1250, 1160, 725, 690 cm-1.

Example 2. Setenil]

Connection receive under option a of the intermediate product (1.b) and 2-methoxybenzylamine. Yield = 72%. Solid white color. So pl. = 228oC. []D= +34o(C = 1, dichloromethane). The analysis is consistent with C25H21N3O3(0,25 H2O).

TLC: S. A3; 0,53.

1NMR, (M. D.): 3.15 in (m, 1H), 3,37 (m, 1H); 4.0 a (m, 1H); 4,08 (s, 3H); of 4.67 (m, 1H); 5,70 (d, 1H, which becomes a singlet due to the exchange); 7,0-to 7.15 (m, 3H): 7,25 (m, 1H); 7,38 (m, 2H); was 7.45 (m, 3H); at 7.55 (m, 2H); of 8.25 (m, 1H); 9,85 (m, 1H exchangeable).

IR-spectrum: 3350, 2900, 1670, 1640, 1590, 1500, 1470, 1380, 1280, 1240, 1170, 1010, 750, 730, 690 cm-1.

Example 2. L: (3R)-3-Methoxy-N-(4-oxo-1-phenyl-3,4,6,7 - tetrahydro-[1,4] diazepino[6,7,1-hi]indol-3-yl)benzamide

[formula (I); A = 3-methoxyphenyl]

Connection receive under option a of the intermediate product (1.b) and 3-methoxybenzylamine. Yield = 74%. Solid white color. So pl. = 181oC. []D= +48o(C = 1, dichloromethane). The analysis is consistent with C25H21N3O3.

TLC: S. A3; 0,51.

1NMR, (M. D.); 3.15 in (m, 1H); to 3.35 (m, 1H); 3,85 (s, 3H); 4.0 a (m, 1H): the 4.65 (m, 1H); the 5.65 (d, 1H, becomes a singlet due to the exchange); 7,10 (m, 2H); 7,25 (m, 1H); 7,35 and 7.6 (m, 9H); 7,97 (m, 1H exchangeable).

IR-spectrum: 3400, 2900, 1650, 1600, 1480, 1500, 1475, 1440, Pino[6,7,1-hi]indol-3-yl)benzamide

[formula (I); A = 4-methoxyphenyl]

Connection receive under option a of the intermediate product (1.b) and 4-methoxybenzylamine. Yield = 67%. Solid white color. So pl. = 221oC (decomposition). []D= +51o(C = 1, dichloromethane). The analysis is consistent with C25H21N3O3.

TLC: S. A3; 0,49.

1NMR, (M. D.): 3,13 (m, 1H); to 3.35 (m, 1H); 3,85 (s, 3H); 4.0 a (m, 1H); with 4.65 (m, 1H); the 5.65 (d, 1H, becomes a singlet due to the exchange); to 6.95 (d, 2H); 7,10 (t, 1H): to 7.25 (t, 1H); 7,38 (m, 2H); was 7.45 (m, 2H); at 7.55 (m, 2H); to 7.95 (m, 3H, of which 1H exchangeable).

IR-spectrum: 3350, 1680, 1650, 1600, 1480, 1390, 1250, 1200, 1030, 840, 760, 725, 695 cm-1.

Example 2. N: (3R)-3,4,5-Trimetoksi-N-(4-oxo-1-phenyl-3,4,6,7 - tetrahydro-[1,4]diazepino[6,7,1-hi]indol-3-yl)benzamide

[formula (I); A = 3,4,5-trimethoxyphenyl]

Connection receive under option b of the intermediate product (1.b) and 3,4,5-trimetoxybenzoic acid. Output = 81,4%. Amorphous solid. So pl. = 221oC (decomposition). []D= +54o(C = 1, dichloromethane). The analysis is consistent with C27H25N3O3.

TLC: S. A4; 0,76.

1NMR, (M. D.): 3.15 in (m, 1H); to 3.35 (m, 1H); 3,90 (d, 9H); 4,00 (m, 1H); with 4.65 (m, 1H); ceiling of 5.60 (d, 1H); 7,10 (m, 1H), 7,15-7,30 (m, 3H), 7,30-of 7.60 (m, 6H); of 7.90 (d, 1H).

IR-spectrum: 3300, 2900, 1640, 1520, 1�-[1,4]diazepino[6,7,1-hi]indol-3-yl)benzamide

[formula (I); A = 2-methoxy-5-chlorophenyl]

Connection receive under option b of the intermediate product (1.b) and 2-methoxy-5-chlorbenzoyl acid. Output = 90,1%. Amorphous solid. So pl. = 234oC. (C = 1, dichloromethane). The analysis is consistent with C25H17ClN3O3.

TLC: S. A3; 0,64.

1H-NMR, (M. D. ): 3.15 in (m, 1H); to 3.35 (m, 1H); 4,00 (m, 1H); 4,10 (s, 3H); 4,70 (m, 1H); 5,6 (d, 1H); 7,00 (d, 1H); 7,10 (t, 1H); 7,20-to 7.50 (m, 6N); at 7.55 (d, 2H); or 8.2 (m, 1H); 9,75 (d, 1H exchangeable).

IR-spectrum: 3350, 1650, 1590, 1470, 1380, 1260, 1240, 1180, 1010, 730, 690, 640 cm-1.

Example 2.P: (3R)-4-Acetamido-N-(4-oxo-1-phenyl-3,4,6,7 - tetrahydro-[1,4] diazepino[6,7,1-hi]indol-3-yl)benzamide

[formula (I); And = acetamidophenyl]

Connection receive under option b and of the intermediate product (1. b) and intermediate pentafluorophenyl ester of 4-acetamido-benzoic acid. Yield = 32%. Amorphous product. So pl. = 266oC. []D= +43o(C = 1, dichloromethane). The analysis is consistent with C16H22N4O3.

TLC: S. B; 0,20.

1NMR, (M. D.): 2,10 (s, 3H); 3.15 in (m, 1H); to 3.35 (m, 1H); 4,00 (m, 1H); with 4.65 (m, 1H); ceiling of 5.60 (d, 1H); 7,10-of 7.60 (m, 8H); the 7.65 (d, 2H); 7.85 (d, 2H); to 7.95 (d, 1H exchangeable); 8,35 (ush.s, 1H exchangeable).

IR-spectrum: 3300, 1690, 1740, 1600, 1510, 1440, 1390, 1310, 1260, 1180, 1120, 1020, 860, Alin-2-carboxylic acid

[formula (I); A = 2-pyridyl]

Connection receive under option b of the intermediate product (1.b) and pyridine-2-carboxylic acid. Output = 86,0%. Amorphous solid. So pl. = 208oC. []D+57o(C = 1, dichloromethane). The analysis is consistent with C23H18N4O20,2 CH2Cl20,1 H2O.

TLC: S. A3; 0,67.

1H-NMR, (M. D. ): 3.15 in (m, 1H); to 3.35 (m, 1H); 4,00 (m, 1H); with 4.65 (m, 1H), 5,65 (d, 1H); 7,10 (m, 1H): 7,20-of 7.60 (m, 8H), the 7.85 (m,1H); to 8.20 (d, 1H); 8,65 (d, 1H): to 9.70 (d, 1H exchangeable).

IR-spectrum: 3300, 1660, 1490, 1440, 1380, 1240, 1160, 750, 690 cm-1.

Example 2. From: (3R)-N-(4-Oxo-1-phenyl-3,4,6,7-tetrahydro- [1,4]diazepino[6,7,1-hi]indol-3-yl)isonicotinamide

[formula (I): A = 4-pyridyl]

Connection receive under option b of the intermediate product (1. b) and intermediate pentafluorophenyl ester of isonicotinic acid. Yield = 83%. Amorphous product. So pl. = 234oC. []D= +23o(C = 1, dichloromethane). The analysis is consistent with C25H20ClN3O3.

TLC: S. A10; 0,60.

1NMR, (M. D.): 3,10 (m, 1H); 3,30 (m, 1H): 3,90 (m, 1H): 4,60 (m, 1H); ceiling of 5.60 (d, 1H); 7,05 is 7.50 (m, 8H, of which 1H exchangeable); to 7.75 (m, 2H); and 8.50 (m, 1H); to 8.70 (m, 2H).

IR-spectrum: 3300, 1640, 1470, 1430, 1380, 1270, 1160, 1110, 1040, 750, 720, 690 cm-1.

PR is ormula (I); A = 2-1H-indolyl]

Connection receive under option a of the intermediate product (1.b) and the acid chloride 1H-indole-2-carboxylic acid. Yield = 81%. Solid white color. So pl. = 196oC. []D= +74o(C = 1, dichloromethane). The analysis is consistent with C26H19N4O20.5 C4H8O2.

TLC: S. A3; 0,62.

1NMR, (M. D.): 2,8-3,6 (m, 2H); 3,7-of 4.25 (m, 1H); 4,4-4,7 (1H); 5,55-the 5.65 (d, 1H, becomes a singlet due to the exchange); the 6.9 to 7.7 (m, 13H); of 7.9 and 8.1 (d, 1H exchangeable); of 10.05 (s, 1H exchangeable).

IR-spectrum: 3250, 1685, 1630, 1530, 1440, 1385, 1340, 1235, 740, 690 cm-1.

Example 2.From: (4-Oxo-1-phenyl-3,4,6,7-tetrahydro- [1,4]diazepino[6,7,1-hi] indol-3-ID)amide (3R)-quinoline-3-carboxylic acid

[formula (I); A = 3-chinolin]

Connection receive under option a of the intermediate product (1.b) and the acid chloride quinoline-3-carboxylic acid. Yield = 65%. Solid white color. So pl. = 150oC. []D= +152o(C = 1, dichloromethane). The analysis is consistent with C27H20N4O20,4 H2O.

TLC: S. A4; 0,22.

1NMR, (M. D.): 2,70-3,6 (m, 2H); 3,6-to 4.15 (m, 1H); 4,3-4,8 (1H); 5.5 to 5.7 (d, 1H becomes a singlet due to the exchange); to 6.8 to 8.3 (m, 13H); 8,60 was 8.8 (m, 1H); 9,2-9,4 (m, 1H).

IR-spectrum: 3300, 1680, 1660, 1510, 1445, 12-the quinoline-6-carboxylic acid [formula (I); A = 6-chinolin]

Connection receive under option a of the intermediate product (1.b) and the acid chloride quinoline-6-carboxylic acid. Yield = 57%. Solid white color. So pl. = 182oC. []D= +59o(C = 1, dichloromethane). The analysis is consistent with C27H20N4O20,75 H2O.

TLC: S. A4, and 0.40.

1H-NMR, (M. D.): 2,80-of 3.60 (m, 2H); 3,70-4,30 (m, 1H); 4,50-of 4.90 (m, 1H); of 5.75 (d, 1H, becomes a singlet due to the exchange); 6,90-of 7.70 (m, 10H); 8,00-to 8.40 (m, 4H, of which 1H exchangeable); 8,55 (m, 1H); 9,00 (m, 1H).

IR-spectrum: 3300, 1680, 1650, 1510, 1490, 1440, 1280, 780, 730, 695 cm-1.

Example 2.X: (4-Oxo-1-phenyl-3,4,6,7-tetrahydro- [1,4]diazepino[6,7,1-hi] indol-3-ID)amide (3R)-2-methyl-quinoline-4 - carboxylic acid

[formula (I); A = 4-(2-medicinalis)]

Connection receive under option b and of the intermediate product (1. b) and intermediate pentafluorophenyl ester 2-methyl - quinoline-4-carboxylic acid. Yield = 94%. Amorphous product. So pl. = 280oC (decomposition). The analysis is consistent with C28H22N4O20,1 CH2Cl2.

TLC: S. A3; 0,58.

1NMR, (M. D.): 2,70 (s, 3H); 3,20 (m, 1H); to 3.45 (m, 1H); 4,00 (m, 1H); 4,70 (m, 1H); 5,80 (d, 1H); 7,10 to 7.75 (m, 11H); 8,15 (d, 1H); to 8.20 (d, 1H exchangeable); cent to 8.85 (s, 1H).

IR-spectrum: 3300, 1650hi] indol-3-yl)amide (3R)-isoquinoline-3-carboxylic acid

[formula (I); A = 3-ethanolic]

Connection receive under option B. b of the intermediate product (1. b) and intermediate pentafluorophenyl ester 3-methyl-quinoline-4-carboxylic acid in the presence of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide. Yield = 84%. Amorphous product. So pl. = 250oC []D= +10o. (C = 1, dichloromethane). The analysis is consistent with C27H20N4O20,3 H2O 0,15 CH2Cl2.

TCX: S. A1; 0,25.

1H-NMR, (M. D.): 3,12 (m, 1H); to 3.38 (m, 1H); 3.75 to (c, 3H), 4,0 (m, 1H); 4,63 (m, 1H), 5,72 (d, 1H, becomes a singlet due to the exchange); for 7.12 (m, 1H); 7,28 (m, 1H); 7,35 (m, 2H); 7,47 (m, 2H); to 7.59 (m, 2H): 7,72 (m, 2H); to 8.0 (d, 1H); 8,1 (d, 1H); 8,65 (s, 1H); 9.28 are (s, 1H); 9,86 (d, 1H exchangeable).

IR-spectrum: 3400, 1670, 1600, 1485, 1450, 1260, 900, 790, 785, 755, 730, 700, 670 cm-1.

The hydrochloride is obtained from the base in hydrochloric acid propanol. The resulting crystals are washed with diethyl ether and dried in vacuum So pl. = 225oC []D= -416o(C = 1, dichloromethane).

TCX: S. A3; 0,35.

Example 2.H: Persulfonic (4-oxo-1-phenyl-3,4,6,7-tetrahydro- [1,4]diazepino[6,7,1-hi] indol-3-yl)amide (3R)-N-methyl - skinline-3-carboxylic acid

[formula (I); A = N-methyl-3-skinline]

1.0 g (2,31 mmol) of the product of example 2.C dissolved in 12 ml of taiwania for 1 hour at 0oC leave the temperature to rise to room temperature and then evaporated under reduced pressure. The residue is purified by flash chromatography on a column of silica, eluting with remedy is a mixture of increasing polarity of acetone in dichloromethane. Obtain 1.1 g of the compound in a solid white color. So pl. = 228oC. Yield = 87%. []D= -408o(C = 1, dichloromethane). The analysis is consistent with C28H23FN4O5S 0,5 H2O.

TCX: S. A10; 0,10.

1H-NMR, (M. D.): the 3.35 (m, 1H); to 3.45 (m, 1H); to 3.52 (s, 3H); 4,5 (m, 1H); 4,78 (m, 1H); of 5.75 (d, 1H, becomes a singlet due to the exchange); 7,0 (m, 1H): 7,25 (m, 1H); 7,45 (m, 1H); the 7.65 (m, 2H); and 7.7 to 7.9 (m, 5H); 8,02 (m, 1H); to 8.12 (s, 1H); 8,65 (s, 1H); a 9.25 (s, 1H); 10,5 (d, 1H exchangeable).

IR-spectrum: 3450, 3350, 1680, 1600, 1560, 1480, 1430, 1270, 1070, 770, 700, 580 cm-1.

Example 2.W: (4-Oxo-1-phenyl-3,4,6,7-tetrahydro-[1,4]diazepino [6,7,1-hi] indol-3-ID)aminimides[1,2-a]pyrimidine-2 - carboxylic acid

[formula (1); And= imidazo[1,2-a]pyrimidinyl]

Connection receive under option B. (a) of the intermediate product (1. b) and intermediate pentafluorophenyl ester imidazo[1,2-a]pyrimidine-2-carboxylic acid. Yield = 57%. Amorphous product. So pl. = 270oC (decomposition). []D= -21o(C = 1, dichloro">

TLC: S. A9; 0,13.

1H-NMR (dimethylsulfoxide), (M. D.): 2,90-3,5 (m, 2H); 3,5-4,20 (m, 1H); from 4.2 to 4.7 (m, 1H): 5,40 to 5.6 (d, 1H, becomes a singlet due to the exchange); of 7.0 to 7.7 (m, 9H); 7,6-7,8 (m, 1H); 8.0 a (s, 1H); 8.6 out of 8.75 (m, 1H); 8,75-8,95 (D. III exchanged).

IR-spectrum: 3400 (extended), 1685, 1645, 1530, 1440, 1280, 1220, 1155, 730, 700 cm-1.

Example 2.Y: (4-Oxo-1-phenyl-3,4,6,7-tetrahydro- [1,4]diazepino[6,7,1-hi] indol-3-yl)amide (3R)-4,7-dimethyl-pyrazole- [5,1-C][1,2,4]triazine-3-carboxylic acid

[formula (I); A = 3-(4,7-dimethyl-pyrazole[5,1-C][1,2,4]triazinyl]

Connection receive under option B. (a) of the intermediate product (1. b) and intermediate pentafluorophenyl ether, 4,7-dimethyl-pyrazole[5,1-C] [1,2,4] triazine-3-carboxylic acid. Yield = 46%. The white powder. So pl. = 260oC. []D= +21o(C=1, dichloromethane). The analysis is consistent with C25H21N7O20,75 H2O.

TLC: S. A3; 0,20.

1H-NMR, (M. D. ): to 2.65 (s, 3H); 3.15 in (m, 1H); 3,30 (s, 3H); 3.40 in (m, 1H); 4,00 (m, 1H); 4,70 (m, 1H); 5,70 (d, 1H); 7,10-of 7.60 (m, 9H); 9,90 (d, 1H exchangeable).

IR-spectrum: 3350, 1660, 1600, 1560, 1470, 1390, 1370, 1300, 1230, 1170, 800, 730, 690, 640 cm-1.

Example 3: (9-Methyl-4-oxo-1-phenyl-3,4,6,7-tetrahydro- [1,4] diazepino[6,7,1-hi]indol-3-yl)amide (3R,S)-quinoline-3-carboxylic acid

[formula (I); A = 3-chinolin; R = enil-6,7-dihydro- [1,4]diazepino[6,7,1-hi]indol-4-it - and the acid chloride quinoline-3 - carboxylic acid. Yield = 56%. Solid white color. So pl. = 238oC. the Analysis is consistent with C28H22N4O20,2 H2O.

TLC: S. A4; 0,18.

1H-NMR, (M. D.): 2,45 (s, 3H); 3,1 (m, 1H); to 3.45 (m, 1H), 3,95 (m, 1H); with 4.65 (m, 1H); 5,71 (d, 1H, becomes a singlet due to the exchange); 7,25-the 7.65 (m, 8H); a 7.85 (m, 1H); to 7.95 (d, 1H); or 8.2 (d, 1H exchangeable); of 8.25 (d, 1H); 8,8 (s, 1H); to 9.45 (s, 1H).

IR-spectrum: 3450 (extended); 3200, 3005, 1690, 1660, 1530, 1430, 1375, 1290, 1245, 1160, 920, 780, 695 cm-1.

Example 4: (9-Methyl-4-oxo-1-phenyl-3,4,6,7-tetrahydro- [1,4] diazepino[6,7,1-hi]indol-3-yl)amide (3R)-isoquinoline-3 - carboxylic acid

[formula (I); A = 3-ethanolic: R = CH3]

Connection receive under option B. b) by the method identical to that of example 2.C., with the use of the intermediate product (2.b): (3R)-3-amino-9-methyl-1-phenyl-6,7-dihydro- [1,4] diazepino[6,7,1-hi] indol-4-it. Yield = 93%. Solid white color. So pl. = 130oC. []D= +8o(C = 1, dichloromethane). The analysis is consistent with C27H20N4O20,4 H2O 0,15 CH2Cl2.

TLC: S. A4; 0,17.

1H-NMR, (M. D.): 2,35 (s, 3H); 3,1 (m, 1H); to 3.35 (m, 1H); 4.0 a (m, 1H): the 4.65 (m, 1H); 5,7 (d, 1H, becomes a singlet due to the exchange); to 7.25-7.5 (m, 5H); 7,6 (m, 2H); to 7.75 (m, 2H); 8 (ASS="ptx2">

Example 5: (9-Methoxy-4-oxo-1-phenyl-3,4,6,7-tetrahydro- [1,4]diazepino[6,7,1-hi]indol-3-yl)amide (3R,S)-isoquinoline-3 - carboxylic acid

[formula (I); A = 3-ethanolic; R = CH3O]

Connection receive under option a of the intermediate product (3.(a) - (3R,S)-3-amino-9-methoxy-1-phenyl-6,7-dihydro- [1,4]diazepino[6,7,1-hi]indol-4-it - and acid chloride of the quinoline-3 - carboxylic acid. Yield = 40%. Solid white color. So pl. = 204oC. the Analysis is consistent with C28H22N4O30,33 H2O 0,33 CH2Cl2.

TCX: S. B1; 0,25.

1H-NMR; (M. p.); 3,1 (m, 1H); to 3.35 (m, 1H); of 3.75 (s, 3H); 4.0 a (m, 1H); 4.7 in (m, 1H), 5,7 (d, 1H, becomes a singlet due to the exchange); 6,7 (ush.s, 1H); 7,1 (ush.s, 1H); 7,25-a 7.85 (m, 7H); to 7.95 (d, 1H); or 8.2 (d, 1H); of 8.25 (d, 1H exchange.); is 8.75 (m, 1H); 9,75 (m, 1H).

IR-spectrum: 3300 (extended), 1660, 1520, 1480, 1390, 1290, 1230, 1120, 780, 700 cm-1.

Example 6. A: (3R)-3-Chloro-N-(9-methoxy-4-oxo-1-phenyl - 3,4,6,7-tetrahydro-[1,4]diazepino[6,7,1-hi]indol-3-yl)benzamide

[formula (I); A = 3 - chlorophenyl; R = CH3O]

Connection receive under option b of the intermediate product (3.b) -(3R)-3-amino-9-methoxy-1-phenyl-6,7-dihydro-[1,4] diazepino [6,7,1-hi] indol-4-it - and 3-chlorbenzoyl acid. Output = 75,9%. Amorphous solid. So pl. = 119oC. []D= +29o1H-NMR, (M. D. ): 3,10 (m, 1H); to 3.35 (m, 1H); 3,70 (s, 3H); 4,00 (m, 1H); with 4.65 (m, 1H); ceiling of 5.60 (d, 1H); 6,70 (s, 1H); 7,10 (s, 1H); 7,35-the 7.65 (m, 7H); a 7.85 (d, 1H); 8,00 (s, 1H); with 8.05 (d, 1H exchange.).

IR-spectrum: 3300, 1660, 1570, 1510, 1460, 1370, 1340, 1260, 1230, 1170, 1140, 1040, 760, 740, 700 cm-1.

Example 6. B: (3R)-4-Chloro-N-(9-methoxy-4-oxo-1-phenyl-3,4,6,7 - tetrahydro-[1,4]diazepino[6,7,1-hi]indol-3-yl)benzamide

[formula (I); A = 4-chlorophenyl; R = CH3O]

Connection receive under option a of the intermediate product (3.b) and 4-chlorobenzylchloride. Yield = 83%. Solid white color. So pl. = 175oC. []D= +3,26o(c=1, dichloromethane). The analysis is consistent with C25H20ClN3O30,25 H2O.

TLC: S. A3; 0,49.

1H-NMR, (M. D.): 3,1 (m, 1H); to 3.35 (m, 1H); of 3.75 (s, 3H); 4.0 a (m, 1H); with 4.65 (m, 1H); 5,6 (d, 1H, becomes a singlet due to the exchange); 6,7 (s, 1H); and 7.1 (s, 1H); 7,35 and 7.6 (m, 7H); to 7.9 (d, 2H); 8.0 a (d, 1H exchange.).

IR-spectrum: 3300, 2900, 1650, 1470, 1365, 1340, 1265, 1230, 1140, 1085, 840, 750, 700 cm-1.

Example 6. In: (3R)-N-(9-Methoxy-4-oxo-1-phenyl-3,4,6,7 - tetrahydro-[1,4] diazepino[6,7,1-hi]indol-3-yl)isonicotinamide

[formula (I); A = 4-pyridyl, R = CH3O]

Connection receive under option B. (a) of intermediate product (3. b) and intermediate pentafluorophenyl ester of isonicotinic acid. Yield = 55%. Am is C24H20H4O30,15 CH2Cl2.

TLC: S. A3; 0,42.

1H-NMR, (M. D. ): 3.15 in (m, 1H); to 3.35 (m, 1H); of 3.75 (s, 3H); 4,00 (m, 1H); with 4.65 (m, 1H); ceiling of 5.60 (d, 1H, becomes a singlet due to the exchange); 6,70 (s, 1H); 7,10 (s, 1H); 7,25-of 7.60 (m, 5H); 7,80 (d, 2H); 8,10 (d, 1H exchange.); 8,80 (d, 2H).

IR-spectrum: 3350, 1685, 1650, 1525, 1570, 1460, 1230, 695 cm-1.

Example 6. G: (9-Methoxy-4-oxo-1-phenyl-3,4,6,7-tetrahydro- [1,4]diazepino-[6,7,1-hi]indol-3-yl)amide(3R)-quinoline-3-carboxylic acid

[formula (I); A = 3-chinolin; R = CH3ON]

Connection receive under option B. b) by the method identical to that of example 2.C., when using the intermediate product (3.b) and intermediate pentafluorophenyl ester quinoline-3-carboxylic acid. Yield = 77%. Solid white color. So pl. = 112oC. []D= +4,6o(C = 1, dichloromethane). The analysis is consistent with C28H22N4O30,66 H2O.

TLC: S. B1; 0,30.

1H-NMR, (M. D.): 3,1 (m, 1H); to 3.35 (m, 1H); of 3.75 (s, 3H); 4.0 a (m, 1H); 4.7 in (m, 1H); 5,7 (d, 1H, becomes a singlet due to the exchange); 6,7 (ush.s, 1H); 7,1 (ush.s, 1H); 7,25-a 7.85 (m, 7H); to 7.95 (d, 1H); or 8.2 (d, 1H): of 8.25 (d, 1H exchange.); is 8.75 (m, 1H); 9,75 (m, 1H).

IR-spectrum: 3300, 1660, 1520, 1480, 1390, 1290, 1230, 1120, 780, 700 cm-1.

Example 6.D: (9-Methoxy-4-oxo-1-phenyl-3,4,6,7-tetrahydro>/BR>Connection receive under option B. b) by the method identical to that of example 2.C., when using the intermediate product (3.b) and intermediate pentafluorophenyl ester quinoline-6-carboxylic acid. Yield = 80%. Solid white color. So pl. = 206oC. []D= +2,95o(C = 1, dichloromethane). The analysis is consistent with C28H22N4O3H2O.

TLC: S. A10; 0,43.

1H-NMR, (M. D.): 3.15 in (m, 1H); 3,4 (m, 1H); of 3.75 (s, 3H); 4.0 a (m, 1H); 4.7 in (m, 1H); the 5.65 (d, 1H, becomes a singlet due to the exchange); 6,7 (s, 1H); and 7.1 (s, 1H); 7,35-the 7.65 (m, 6N); 8,2-8,35 (m, 4H, 1H exchange.); of 8.5 (s, 1H); 9 (m, 1H).

IR-spectrum: 3400 (extended), 1650, 1470, 1370, 1345, 1270, 1230, 1190, 1140, 840, 780, 700 cm-1.

Example 6. E: (9-Methoxy-4-oxo-1-phenyl-3,4,6,7-tetrahydro- [1,4]diazepino[6,7,1-hi]indol-3-yl)amide(3R)-isoquinoline-3 - carboxylic acid

[formula (I); A = 3-ethanolic; R = CH3O]

Connection receive under option B. b) by the method identical to that of example 2.C., when using the intermediate product (3.b) and intermediate pentafluorophenyl ester isoquinoline-3-carboxylic acid. Yield = 87%. Solid white color. So pl. = 211oC. []D= +0,30o(C = 1, dichloromethane). The analysis is consistent with C28H22N2O 0,1 H); the 4.7 (m, 1H): 5,7 (d, 1H, becomes a singlet due to the exchange); 6,7 (ush.(C) and 7.1 (ush.s, 1H); 7,2-7,8 (m, 7H); 8,0 (m, 1H); 8,1 (m, 1H); 8,65 (s, 1H); and 9.3 (s, 1H); 9,9 (d, 1H exchange.).

IR-spectrum: 3360, 1665, 1500, 1490, 1470, 1345, 1265, 1225, 1145, 700 cm-1.

Example 6. W: (9-Methoxy-4-oxo-1-phenyl-3,4,6,7-tetrahydro- [1,4]diazepino-[6,7,1-hi] indol-3-yl)amide (3R)-4,7-dimethyl - pyrazolo-[5,1-C] [1,2,4] triazine-3-carboxylic acid

[formula (I); A = 3-(4,7-dimethyl-pyrazole[5,1-C][1,2,4]tri-azinyl); R = CH3O]

Connection receive under option At an intermediate product (3. b) and 4,7-dimethyl-pyrazole-[5,1 - C][1,2,4]triazine-3-carboxylic acid. Output = 60,9%. Amorphous solid. So pl. = 95oC. []D= +19,6o(C=1, dichloromethane). The analysis is consistent with C26H23N7O3.

TLC: S. A9; 0,82.

1H-NMR, (M. D. ): 2,60 (s, 3H); 3,05 (m, 1H); of 3.25 (s, 3H); 3,30 (m, 1H); the 3.65 (s, 3H); 3,90 (m, 1H); 4,60 (m, 1H); ceiling of 5.60 (d, 1H); 6,60 (s, 1H); 7,00 (s, 2H); 7,25 was 7.45 (m, 3H); at 7.55 (m, 2H); 9,80 (d, 1H exchange.).

IR-spectrum: 3350, 1670, 1570, 1530, 1490, 1440, 1370, 1350, 1300, 1260, 1230, 1140, 1040, 800, 780, 740, 700 cm-1.

Example 7.A: (3R)-2,4-Debtor-N-(4-oxo-1-phenyl-3,4,6,7 - tetrahydro-[1,4] diazepino[6,7,1-hi]indol-3-yl)benzamide

[formula (I); A = 2,4-differenl]

Connection receive under option a of the intermediate product (1.b) and 2.4 Harmattan). The analysis is consistent with C24H17N3O2F2.

TLC: S. A3; 0,83.

1H-NMR, (M. D.): 3.15 in (m, 1H); to 3.35 (m, 1H); 4.0 a (m, 1H); with 4.65 (m, 1H): of 5.55 (d, 1H); to 6.95 (m, 1H); 7,0 (m, 1H); for 7.12 (m, 1H); 7,25 (m, 1H); 7,35 (m, 2H); was 7.45 (m, 2H); 7,53 (m, 2H); 8,15 (m, 1H); of 8.50 (m, 1H exchange.).

Example 7.B: (3R)-2.5-Debtor-N-(4-oxo-1-phenyl-3,4,6,7 - tetrahydro-[1,4] diazepino[6,7,1-hi]indol-3-yl)benzamide

[formula (I); A = 2.5-differenl]

Connection receive under option a of the intermediate product (1.b) and 2.5-differentiald. Yield = 92%. Solid white color. So pl. = 187oC. []D= +42o(C=1, dichloromethane). The analysis is consistent with C24H17N3O2F2.

TLC: S. A3; 0,80.

1H-NMR, (M. D. ): 3,14 (m, 1H); to 3.35 (m, 1H); 3,95 (m, 1H); with 4.65 (m, 1H); 5,13 (d, 1H); to 7.15 (m, 3H); 7,25 (m, 1H); 7,35 (m, 2H); was 7.45 (m, 2H); at 7.55 (m, 2H); 7,80 (m, 1H); to 8.6 (m, 1H exchange.).

Example 7.In: (3R)-3,4-Debtor-N-(4-oxo-1-phenyl-3,4,6,7 - tetrahydro-[1,4] diazepino[6,7,1-hi]indol-3-yl)benzamide

[formula (I); A = 3,4-differenl]

Connection receive under option a of the intermediate product (1.b) and 3,4-differentiald. Yield = 77%. Solid white color. So pl. = 236oC. []D= +46o(C = 1, dichloromethane). The analysis is consistent with C24H17N3O2F2(m, 2H); 7,35 (m, 2H); was 7.45 (m, 2H); at 7.55 (m, 2H); 7,72 (m, 1H); of 7.82 (m, 1H); to 7.95 (d, 1H exchange.).

IR-spectrum: 3300, 1680, 1630, 1600, 1540, 1500, 1280, 1250, 780, 690 cm-1.

Example 7.G: (3R)-3,5-Debtor-N-(4-oxo-1-phenyl-3,4,6,7 - tetrahydro-[1,4] diazepino[6,7,1-hi]indol-3-yl)benzamide

[formula (I); A = 3,5-differenl]

Connection receive under option a of the intermediate product (1.b) and 3.5-differentiald. Yield = 90%. Solid pale yellow color. So pl. = 279oC. []D= +44o(C = 1, dichloromethane). The analysis is consistent with C24H17N3O2F2.

TLC: S. A3; 0,70.

1H-NMR, (M. D.): 3.15 in (m, 1H); to 3.35 (m, 1H); 4.0 a (m, 1H); with 4.65 (m, 1H); ceiling of 5.60 (d, 1H); to 6.95 (m, 1H); 7,10 (m, 1H); of 7.48 (m, 2H); was 7.45 (m, 6H); to 8.0 (d, 1H exchange.).

IR-spectrum: 3200, 1680, 1640, 1590, 1540, 1440, 1380, 1300, 1120, 990, 840, 690 cm-1.

Example 7.D: (3R)-2,4-Dichloro-N-(4-oxo-1-phenyl-3,4,6,7-tetrahydro-[1,4] diazepino[6,7,1-hi]indol-3-yl)benzamide

[formula (I); A = 2,4-dichlorophenyl]

Connection receive under option a of the intermediate product (1.b) and 2,4-dichlorobenzotrifluoride. Yield = 77%. Solid yellowish color. So pl. = 186oC. []D= +78o(C= 1, dichloromethane). The analysis is consistent with C24H17N3O2Cl2.

TLC: S. A3; 0,64.

1the Myung.).

Example 7.E: (3R)-3,5-Dichloro-N-(4-oxo-1-phenyl-3,4,6,7 - tetrahydro-[1,4] diazepino[6,7,1-hi]indol-3-yl)benzamide

[formula (I); A = 3,5-dichlorophenyl]

Connection receive under option a of the intermediate product (1.b) and 3.5-dichlorobenzotrifluoride. Yield = 65%. Solid yellow color. So pl. = 211oC. []D= +46o(C = 1, dichloromethane). The analysis is consistent with C24H17N3O2Cl2.

TLC: S. A3; 0,85.

1H-NMR, (M. D. ): 3,12 (m, 1H); to 3.35 (m, 1H); 3,95 (m, 1H); with 4.65 (m, 1H); to 5.56 (d, 1H); 7,10 (m, 1H); 7,20 (m, 1H); 7,35 (m, 1H); was 7.45 (m, 6H); 7,8 (s, 2H); to 8.12 (d, 1H exchange.).

IR-spectrum: 3300, 1680, 1650, 1560, 1530, 1440, 1400, 1280, 1240, 1120, 800, 700 cm-1.

Example 7. W: (3R)-3,5-bis(Trifluoromethyl)-N-(4-oxo-1-phenyl - 3,4,6,7-tetrahydro-[1,4]diazepino[6,7,1-hi]indol-3-yl)-benzamide

[formula (I); A = 3,5-bis(trifluoromethyl)phenyl]

Connection get under way And from the intermediate product (1.b) and 3,5-bis(trifluoromethyl)benzoyl chloride. Yield = 92%. Solid yellowish color. So pl. = 208oC. []D= +46o(C=1, dichloromethane). The analysis is consistent with C26H17N3O2F6.

TLC: S. A3; 0,88.

1H-NMR, (M. D.): 3,5 (m, 1H); to 3.35 (m, 1H); 3,98 (K, 1H); with 4.65 (m, 1H); ceiling of 5.60 (d, 1H); for 7.12 (m, 1H); 7,25 (m, 2H); 7,35 (m, 2H); was 7.45 (m, 2H); 7,52 (m, 2H); 7,22 (m, is 7.3: (3R)-3,4-Dimethoxy-N-[-(4-oxo-1-phenyl-3,4,6,7 - tetrahydro-[1,4]diazepino[6,7,1-hi]indol-3-yl)benzamide

[formula (I); A = 3,4-acid]

Connection receive under option a of the intermediate product (1.b) and 3,4-dimethoxybenzaldehyde. Yield = 91%. Solid white color. So pl. = 144oC. []D= +54o(C = 1, dichloromethane). The analysis is consistent with C26H23N3O4.

TLC: S. A3; 0,33.

1H-NMR, (M. D. ): 3.15 in (m, 1H); to 3.35 (m, 1H); 3,95 (d, 6H); 3,95 (m, 1H); with 4.65 (t, 1H); the 5.65 (d, 1H); 6.90 to (d, 1H); 7,10 (t, 1H); to 7.35 (t, 2H); was 7.45 (m, 2H); at 7.55 (m, 4H); to 7.95 (d, 1H exchange.).

IR-spectrum: 3300, 1680, 1650, 1600, 1490, 1440, 1260, 1220, 1020, 760, 700 cm-1.

Example 7. And: (3R)-3-Chloro-4-methoxy-N-(4-oxo-1-phenyl-3,4,6,7 - tetrahydro-[1,4]diazepino[6,7,1-hi]indol-3-yl)benzamide

[formula (I); A = 3-chloro-4-methoxyphenyl]

Connection receive under option b of the intermediate product (1.b) and 3-chloro-4-methoxy-benzoic acid. Yield = 82%. Solid pink color. So pl. = 158oC. []D= +50o(C = 1, dichloromethane). The analysis is consistent with C25H20N3O3Cl.

TLC: S. A3; 0,60.

1H-NMR, (M. D.): 3,12 (m, 1H); to 3.35 (m, 1H); of 3.95 (s, 3H); 4.0 a (m, 1H); 5,10 (d, 1H); to 6.95 (d, 1H); 7,10 (t, 1H); 7,25 (m, 1H); 7,35 (m, 2H); the 7.43 (m, 2H); to 7.50 (m, 2H); a 7.85 (m, 1H); to 7.95 (m, 1H exchange.); 8,15 (d, 1H).

IR-spectrum: 3300, 1650, 1600, 1480, 1440, 1390, 1260, 1060, 760, 700 cm-1.

When the(I): A = 4-amino-3,5-dichlorophenyl]

Connection receive under option b of the intermediate product (1.b) and 4-amino-3,5-dichlorobenzoyl acid. Yield = 90%. Solid light pink color. So pl. = 168oC. []D= +54o(C = 1, dichloromethane). The analysis is consistent with C24H18N4O2Cl2.

TLC: S. A3; 0,62.

1H-NMR, (M. D.): 7,9 (s, 1H); and 7.3 (m, 8H); and 5.6 (d, 1H) and 4.9 (s, 2H); 4.7 in (t, 1H); 4 (K, 1H); 3,4 (m, 1H); 3,1 (m, 1H).

IR-spectrum: 3300, 1600, 1520, 1470, 1390, 1350, 1280, 1120, 780, 700 cm-1.

Example 7.L: (3R)-2-Acetamido-N-(4-oxo-1-phenyl-3,4,6,7 - tetrahydro-[1,4] diazepino[6,7,1-hi]indol-3-yl)benzamide

[formula (I); A = 2-acetamido-phenyl]

Connection receive under option b of the intermediate product (1.b) and N-acetylanthranilic acid. Yield = 27%. Solid white color. So pl. = 210oC. []D= 46o(C = 1, dichloromethane). The analysis is consistent with C26H22N4O3.

TLC: S. A9; 0,26.

1H-NMR, (M. D.): 1,75 (ush.with exchanged); 2,85 (s, 3H); 3.15 in (m, 1H); 3,4 (m, 1H); 4.0 a (m, 1H); 4,22 (m, 1H); for 7.12 (m, 1H); 7,20 (s, 1H); 7,25 (m, 1H); 7,45 (5H); at 7.55 (d, 2H); to 7.75 (m, 2H); or 8.2 (d, 1H).

Example 7.M: (3R)-2-Acetoxy-N-(4-oxo-1-phenyl-3,4,6,7 - tetrahydro-[1,4] diazepino[6,7,1-hi]indol-3-ID)benzamide

[formula (I); A = 2-acetoxy-phenyl]

The connection isC. []D= +57o(C = 1, dichloromethane). The analysis is consistent with C26H21O4N3.

TLC: S. A3; 0,50.

1H-NMR, (M. D.): a 2.5 (s, 3H); of 3.12 (m, 1H); to 3.36 (m, 1H); 3,95 (K, 1H); 4,5 (t, 1H); 5,63 (d, 1H); and 7.1 (t, 1H); 7.7 (d, 1H); 7,25 (m, 1H); 7,35 (m, 3H); was 7.45 (m, 2H); a 7.62 (m, 3H); 8,18 (d, 1H); 8,48 (d, 1H exchange.).

IR-spectrum: 3400, 1760, 1660, 1600, 1500, 1180, 1090, 910, 730, 700 cm-1.

Example 7. N: Potassium salt of (3R)-2-hydroxy-N-(4-oxo-1-phenyl - 3,4,6,7-tetrahydro-[1,4]diazepino[6,7,1-hi]indol-3-yl)-benzamide

[formula (I); A = potassium-2-feat]

The ester function of the product of example 7.M omelet using potassium hydroxide in methanol at boiling under reflux for two hours, then the solvent is evaporated. Yield = 89%. Solid yellow color. So pl. = 243oC. []D= +4o(C = 1, dichloromethane). The analysis is consistent with C24H18O3N3K 2,5 H2O.

TLC: S. A3; 0,67.

1H-NMR, (M. D.): and 3.16 (m, 1H); to 3.35 (m, 1H); 3,5 (HzO); 3,92 (K, 1H); to 4.98 (t, 1H); 5,1 (s, 1H); 6,3 (t, 1H); 6.75 in (d, 1H); 7,02 (m, 1H); to 7.2 (m, 2H): 12.7mm (1H, ush., currency.); of 7.48 (m, 5H); 7,6 (m, 1H), and 7.7 (m, 1H).

Example 7.O: (3R)-5,6-Dichloro-N-(4-oxo-1-phenyl-3,4,6,7 - tetrahydro-[1,4] diazepino[6,7,1-hi]indol-3-yl)nicotinamide

[formula (I); A = 3-(5,6-dichloropyridine)]

Connection receive according to Varian is. the l = 138-140oC. []D= +43,7o(C = 1, dichloromethane). The analysis is consistent with C23H16Cl2N4O2.

TLC: S. A3; 0,30.

1H-NMR, (M. D.): 3,1-of 3.25 (m, 1H); 3,3-3,5 (m, 1H); 3.95 to 4,1 (K, 1H); 4,6-of 4.75 (t, 1H); at 5.5 to 5.6 (d, 1H); a 7.1 to 7.6 (m, 8H); 8,1 is 8.25 (d, 1H); 8,25-8,35 (s, 1H); 8,75-8,9 (s, 1H).

IR-spectrum: 3250, 1650, 1520, 1360, 1290, 1240, 1150, 1040, 760, 690 cm-1.

Example 7.P: (3R)-3,5-Dichloro-N-(4-oxo-1-phenyl-3,4,6,7 - tetrahydro-[1,4] diazepino[6,7,1-hi]indol-3-yl)isonicotinamide

[formula (I); A = 3,5-dichloro-4-pyridyl]

Connection receive under option b of the intermediate product (1.b) and 3.5-dichlorophenylamino acid. Yield = 18%. Solid white color. So pl. = 182oC. []D= +136,5o(C = 1, dichloromethane). The analysis is consistent with C23H16Cl2N4O2.

TLC: S. A10; 0,45.

1H-NMR, (M. D.): 3,1-of 3.25 (m, 1H); at 3.35 to 3.5 (m, 1H); 3,9-4,1 (m, 1H); 4,6-of 4.75 (m, 1H); 5,6-5,7 (d, 1H); a 7.1 to 7.6 (m, 8H); 7,7-a 7.85 (d, 1H); an 8.5 and 8.6 (d, 2H).

IR-spectrum: 3300, 1670, 1600, 1520, 1390, 1280, 1200, 880, 820, 700 cm-1.

Example 7. R.: (3R)-3-tert.-Butyloxycarbonyl-N-(4-oxo-1 - phenyl-3,4,6,7-tetrahydro-[1,4]diazepino[6,7,1-hi]in DoD-3-yl)isonicotinamide

[formula (I); A = 3-tert.-butyloxycarbonyl-4-pyridyl]

Connection get in dimethylformamide coz the ukta (1.b) and N-Boc-derivative of 3-amino-isonicotinic acid. Yield = 67%. Solid yellow color.

TLC: S. A10, and 0.40.

1H-NMR, (M. D.): 1,45 (s, 9H); 3.15 in (m, 1H), 3,4 (m, 1H); 3,95 (K, 1H); 4,5 (t, 1H); of 5.45 (d, 1H); 7.5 (m, 9H): 8,4 (d, 1H); 9,35 (s, 1H); 9,9 (s, 1H); 10,2 (d, 1H).

Example 7. From: (3R)-3-Amino-N-(4-oxo-1-phenyl-3,4,6,7 - tetrahydro-[1,4] diazepino[6,7,1-hi]indol-3-yl)isonicotinamide

[formula (I); And-3-amino-4-pyridyl]

Of the condensation product obtained in the preceding example 7.R, remove the N-protective group using triperoxonane acid in dichloromethane. After stirring for 30 minutes at room temperature the solvent is removed, the residue treated with ethyl acetate and the resulting solution was extracted with saturated solution of sodium bicarbonate. After drying the solvent is evaporated and the residue purified by column chromatography on silica, elwira a mixture of dichloromethane with methanol in the ratio of 98:2 by volume. Yield = 68%. Solid beige color. So pl. = 175oC.

TLC: S. B; 0,15.

1H-NMR, (M. D.): 3.15 in (m, 1H); 3,4 (m, 1H): 3,95 (K, 1H); 4,5 (t, 1H), and 5.5 (d, 1H); of 5.75 (s, 1H); of 6.45 (s, 1H); 7.5 (m, 9H); or 8.2 (s, 1H); 9,7 (d, 1H).

IR-spectrum: 3300. 2900. 1680, 1640, 1600, 1580, 1500, 1230, 1040, 700 cm-1.

Example 7.T: (3R)-3-Acetamido-N-(4-oxo-1-phenyl-3,4,6,7 - tetrahydro-[1,4] diazep the RA 7.With dissolved in 2 ml of pyridine; add 1 ml of acetic anhydride and before adding 10 ml of water the mixture is stirred for 12 hours at room temperature. After stirring for 4 hours at room temperature (after adding water) the mixture is extracted with ethyl acetate; the organic phase is washed with a saturated solution of sodium bicarbonate, then dried. After evaporation the residue is purified by column chromatography on silica, elwira mixture of increasing polarity of acetone in dichloromethane. Yield = 45%. Solid white color. So pl. = 190oC.

TLC: S. B; 0,17.

1H-NMR, (M. D.): 2,2 (s, 3H); 3,2 (m, 1H); 3,4 (m, 1H); 4 (K, 1H); 4.7 in (t, 1H); 5,6 (d, 1H); and 7.3 (m, 9H); and 8.3 (d, 1H); to 8.45 (d, 1H); 9,9 (s, 1H); to 10.5 (s, 1H).

IR-spectrum: 3300, 1680, 1650, 1600, 1560, 1500, 1410, 1280, 1240, 700 cm-1.

Example 7. From: (3R)-3-Cyclopropanecarbonyl-N-(4-oxo-1 - phenyl-3,4,6,7-tetrahydro-[1,4]diazepino[6,7,1-hi]indol-3-yl)- isonicotinamide

[formula (I); A = 3 cyclopropanecarbonyl-4-pyridyl]

0.15 g (0.38 mmol) of the product of example 7.With dissolved in 2 ml of dichloromethane; add 1 equivalent of triethylamine. Cool and when the temperature is below 5oC add 40 mg (0.38 mmol) of cyclopropanecarbonitrile. Stirred for 16 hours at room temperature the Oia of the solvent the residue is purified by column chromatography on silica, elwira mixture S. A8. Output = -20%.

TLC: S. A10; 0,17.

1H-NMR, (M. D.): 0,85 (m, 2H); 1,1 (m, 2H); 1,6 (m, 1H); 3.15 in (m, 1H); 3,4 (m, 1H); 4 (K, 1H); 4.7 in (t, 1H); 5,6 (d, 1H); and 7.3 (m, 9H); and 8.3 (d, 1H); and 8.4 (d, 1H); 9,9 (s, 1H); 10,35 (s, 1H).

Example 7.F: (4-Oxo-1-phenyl-3,4,6,7-tetrahydro-[1,4]diazepino[6,7,1-hi] indol-3-yl)amide (3R)-pyrazin-2-carboxylic acid

[formula (I); A = 2-pyrazinyl]

Connection receive under option b of the intermediate product (1.b) and pyrazin-2-carboxylic acid. Yield = 72%. Solid light orange color. So pl. = 213-214oC. []D= +56o(C = 1, dichloromethane). The analysis is consistent with C22H17N5O2.

TLC: S. A10; 0.75 in.

1H-NMR, (M. D.): 3,1-of 3.25 (m, 1H); 3,3-3,5 (m, 11^; 3,9-4,1 (m, 1H); 4,6-of 4.75 (m, 1H); 5,55-5,7 (d, 1H), and 7.7 (m, 8H); 8.6 out of 8.7 (d, 1H); 8,7 cent to 8.85 (d, 1H); 9,35, and 9.6 (M, 2H).

IR-spectrum: 3370, 1670, 1600, 1510, 1450, 1390, 1020, 800, 690 cm-1.

Example 7.X: (4-Oxo-1-phenyl-3,4,6,7-tetrahydro-[1,4]diazepino [6,7,1-hi] indol-3-yl)amide (3R)-thiophene-2-carboxylic acid

[formula); A = 2-thienyl]

Connection receive under option b of the intermediate product (1.b) and thiophene-2-carboxylic acid. Yield = 57%. Solid white color. So pl. = 217 - 218oC. []D= +56o(C = 1, dichloromethane). The analysis is consistent with C221H); 4,6-of 4.75 (m, 1H); 5.5 to 5.7 (d, 1H); 7.0 and about 7.6 (m, 10H); the 7.65 to 7.75 (d, 1H); 7,75 was 7.9 (d, 1H).

IR-spectrum; 3250, 1690, 1630, 1540, 1440, 1380, 1270, 1160, 710, 520 cm-1.

Example 8. A: (4-Oxo-1-phenyl-3,4,6,7-tetrahydro-[1,4]diazepino[6,7,1 - hi]indol-3-yl)amide (3R)-4-chloro-quinoline-3-carboxylic acid

[formula (I); A = 3-(4-chloro-chinolin)]

Connection receive under option B, described in example 1.B, of the intermediate product (1.b) and 4-chloro-quinoline-3-carboxylic acid. Yield = 27%. Solid orange color. So pl. = 192oC. the Analysis is consistent with C27H19ClN4O2.

TLC: S. B; 0,48.

1H-NMR, (M. D.): 3,1 (m, 1H); to 3.35 (m, 1H); 3.9 to (K, 1H); 4,6 (t, 1H); 5,6 (d, 1H); and 7.3 (m, 8H); and 7.6 (t, 1H), and 7.7 (t, 1H); 8,1 (d, 1H); of 8.25 (d, 1H); 8,35 (d, 1H); to 9.15 (s, 1H).

IR-spectrum: 3200, 1650, 1600, 1500, 1440, 1340, 1240, 840, 760, 700 cm-1.

Example 8.B: (4-Oxo-1-phenyl-3,4,6,7-tetrahydro- [1,4]diazepino[6,7,1-hi] indol-3-yl)amide (3R)-4-chloro-6-fluoro - quinoline-3-carboxylic acid

[formula (I); A = 3-(4-chloro-6-fluoro-chinolin)]

Connection receive under option B, described in example 1.B, of the intermediate product (1.b) and 4-chloro-6-fluoro - quinoline-3-carboxylic acid. Yield = 29%. Solid orange color. So pl. = 191oC. []D= +93o(C=1, dichloromethane). The analysis is consistent with C27HieC to 7.3 (m, 9H); to 7.9 (d, 1H); 8,1 (d, 1H); or 8.2 (d, 1H); and 9.1 (s, 1H).

IR-spectrum: 3250, 1660, 1600, 1580, 1490, 1440, 1340, 1295, 830, 700 cm-1.

Example 8.B: (4-Oxo-1-phenyl-3,4,6,7-tetrahydro-[1,4]diazepino[6,7,1-hi] indol-3-yl)amide (3R)-4,6-dichloro-quinoline-3-carboxylic acid

[formula (I); A = 3-(4,6-dichloro-chinolin)]

Connection receive under option B, described in example 1.B, of the intermediate product (1. b) and 4,6-dichloro-quinoline-3-carboxylic acid. Yield = 31%. Solid yellow color. So pl. = 200o. []D= +89o(C = 1, dichloromethane). The analysis is consistent with C27H18Cl2FN4O2.

TLC: S. B; 0,55.

1H-NMR, (M. D.): 3,2 (m, 1H); 3,4 (m, 1H); 4 (K, 1H); 4.7 in (t, 1H); 5,7 (d, 1H); and 7.3 (m, 8H); 7.7 (d, 1H); 8,1 (d, 1H); 8,35 (m, 2H); and 9.2 (s, 1H).

IR-spectrum: 3500, 1660, 1600, 1580, 1480, 1440, 1330, 1240, 820, 700 cm-1.

Example 8.G: (4-Oxo-1-phenyl-3,4,6,7-tetrahydro- [1,4]diazepino[6,7,1-hi] indol-3-yl)amide (3R)-4,8-dichloro-quinoline-3 - carboxylic acid

[formula (I); A = 3-(4,8-dichlorphenol)]

Connection receive under option B, described in example 1.B, of the intermediate product (1. b) and 4,8-dichloro-quinoline-3-carboxylic acid. Yield = 33%. Solid yellow color. So pl. = 225oC. []D= +81o(C = 1, dichloromethane). The analysis is consistent with C27

IR-spectrum: 3200, 1660, 1600, 1510, 1465, 1440, 1390, 1340, 750, 700 cm-1.

Example 8.D: (4-Oxo-1-phenyl-3,4,6,7-tetrahydro-[1,4]- diazepino[6,7,1-hi]indol-3-ID)amide (3R)-4-chloro-6-bromo-quinoline-3 - carboxylic acid

[formula (I); A = 3-(4-chloro-6-bromo-chinolin)]

Connection receive under option B, described in example 1.B, of the intermediate product (1.b) and 4-chloro-6-bromo-quinoline-3-carboxylic acid. Yield = 33%. Solid yellow color. So pl. = 191oC. []D= +86o(C = 1, dichloromethane). The analysis is consistent with C27H18BrClN4O20.5 H2O.

TLC; S. B; 0,70.

1H-NMR, (M. D.): 3.15 in (m, 1H); to 3.45 (m, 1H); 4 (K, 1H); 4.7 in (t, 1H); 5,7 (d, 1H); and 7.3 (m, 8H); to 7.9 (d, 1H); 8 (d, 1H); and 8.4 (d, 1H); 8,55 (s, 1H); and 9.2 (s, 1H).

IR-spectrum: 3250, 1660, 1600, 1580, 1500, 1470, 1330, 1220, 820, 700 cm-1.

Example 8.E: (4-Oxo-1-phenyl-3,4,6,7-tetrahydro-[1,4]diazepino[6,7,1-hi] indol-3-yl)amide (3R)-4-chloro-6-methyl-quinoline-3-carboxylic acid

[formula (I); A = 3-(4-chloro-6-methyl-chinolin)].

Connection receive under option b in the presence of TOTU and diisopropylethylamine on the basis of the intermediate product (1.6) and 4-chloro-6-methyl-quinoline-3-carboxylic acid. Yield = 29%. Solid yellow the SUB>2
0,33 H2O.

TLC: S. B; 0,55.

1H-NMR, (M. D.): 2,6 (s, 1H); 3,2 (m, 1H); 3,4 (m, 1H); 4 (K, 1H); 4.7 in (t, 1H); 5,7 (d, 1H); to 7.4 (m, 9H); with 8.05 (d, 1H); 8,1 (s, 1H); and 8.4 (d, 1H); and 9.1 (s, 1H).

IR-spectrum: 3250, 1650, 1600, 1580, 1490, 1440, 1340, 1240, 820, 700 cm-1.

Example 8.W: (4-Oxo-1-phenyl-3,4,6,7-tetrahydro-[1,4]diazepino [6,7,1-hi] indol-3-yl)amide (3R)-4-chloro-8-methyl-quinoline-3 - carboxylic acid

[formula (I); A = 3- (4-chloro-8-methyl-chinolin)]

Connection receive under option B, described in example 1.B, of the intermediate product (1. b) and 4-chloro-8-methyl-quinoline-3 - carboxylic acid. Output = 30%. Solid yellow color. So pl. = 240oC (decomposition). []D= +82o(C = 1, dichloromethane). The analysis is consistent with C28H21ClN4O3.

TLC: S. B; 0,76.

1H-NMR, (M. D.): 3,1 (m, 1H); 3,4 (m, 1H); 3.9 to (K, 1H); 4,6 (t, 1H); 5,6 (d, 1H); and 7.3 (m, 10H); 8,15 (d, 1H); 8.3 (l, 1H); and 9.1 (s, 1H).

IR-spectrum: 3200, 1660, 1600, 1520, 1440, 1350, 1240, 830, 760, 700 cm-1.

Example 8.C: (4-Oxo-1-phenyl-3,4,6,7-tetrahydro- [1,4]diazepino[6,7,1-hi] indol-3-yl)amide (3R)-4-chloro-6-methoxy - quinoline-3-carboxylic acid

[formula (I); A = 3-(4-chloro-6-methoxy-chinolin)]

Connection receive under option B, described in example 1.B, of the intermediate product (1.b) and 4-chloro-6-methoxy-Hino is dichloromethane). The analysis is consistent with C26H21ClN4O3.

TLC: S. B; 0,55.

1H-NMR, (M. D.): 3,1 (m, 1H); 3,4 (m, 1H); 4 (m, 4H); 4.7 in (t, 1H); 5,7 (d, 1H); and 7.3 (m, 10H); 8,1 (d, 1H); 8.3 (l, 1H); 9,05 (s, 1H).

IR-spectrum: 3250, 1640, 1580, 1530, 1490, 1440, 1400, 1230, 820, 700 cm-1.

Example 8.And: (4-Oxo-1-phenyl-3,4,6,7-tetrahydro- [1,4]diazepino[6,7,1-hi] indol-3-ID)amide (3R)-4-chloro-8-methoxy - quinoline-3-carboxylic acid

[formula (I); A = 3-(4-chloro-8-methoxy-chinolin)]

Connection receive under option B, described in example 1.B, of the intermediate product (1.b) and 4-chloro-8-methoxy-quinoline-3-carboxylic acid. Output = 30%. Solid yellow color. So pl. = 265oC. []D= +91o(C = 1, dichloromethane). The analysis is consistent with C28H21ClN4O3.

TLC: S. B; 0,20.

1H-NMR, (M. D.): 3,05 (m, 1H); 3,3 (m, 1H); 3,95 (K, 1H); of 4.05 (s, 3H); 4,6 (t, 1H); 5,6 (d, 1H); and 7.3 (m, 10H); 7,8 (d, 1H); or 8.2 (d, 1H); and 9.1 (s, 1H).

IR-spectrum: 3200, 1655, 1600, 1520, 1360, 1270, 1180, 800, 700 cm-1.

Example 8.K: (4-Oxo-1-phenyl-3,4,6,7-tetrahydro- [1,4]diazepino[6,7,1-hi] indol-3-yl)amide (3R)-4-chloro-5,7-dimethyl - quinoline-3-carboxylic acid

[formula (I); A = 3-(4-chloro-5,7-dimethyl-chinolin)]

Connection receive under option B, described in example 1.B, an intermediate product>. []D= +118o(C = 1, dichloromethane). The analysis is consistent with C29H23ClN4O2.

TLC: S. B; 0,55.

1H-NMR, (M. D.): 2,4 (s, 3H); 2,9 (s, 3H); 3,05 (m, 1H); 3,3 (m, 1H); 3.9 to (K, 1H); 4,6 (t, 1H); 5,6 (d, 1H); and 7.3 (m, 9H), and 7.7 (s, 1H); 8 (d, 1H); and 8.4 (s, 1H).

IR-spectrum: 3250, 1680, 1660, 1600, 1580, 1520, 1440, 1220, 700 cm-1.

Example 8.L: (4-Oxo-1-phenyl-3,4,6,7-tetrahydro-[1,4]diazepino [6,7,1-hi] indol-3-yl)amide (3R)-4-chloro-5,8-dimethyl-quinoline-3 - carboxylic acid

[formula (I); A = 3-(4-chloro-5,8-dimethyl-chinolin)]

Connection receive under option B, described in example 1.In, of the intermediate product (1. b) and 4-chloro-5,8-dimethyl - quinoline-3-carboxylic acid. Output = 30%. Solid beige color. So pl. = 240oC (decomposition). []D= +76o(C = 1, dichloromethane). The analysis is consistent with C29H23ClN4O2.

TLC: S. B; 0,80.

1H-NMR, (M. D.): 3,05 (m, 1H); 3,3 (m, 1H); 3,8 (K, 1H); 4,6 (t, 1H); 5,6 (d, 1H); and 7.3 (m, 10H); 8,1 (d, 1H); 8,9 (s, 1H).

IR-spectrum: 3250. 1660, 1600, 1520, 1440, 1390, 1220, 830, 730, 700 cm-1.

Example 8.M: (4-Oxo-1-phenyl-3,4,6,7-tetrahydro- [1,4]diazepino[6,7,1-hi] indol-3-yl)amide (3R)-4-chloro-6,8-dimethyl - quinoline-3-carboxylic acid

[formula (I); A = 3-(4-chloro-5,8-dimethyl-chinolin)]

Connection receive according to variations is. yhad = 25%. Solid white color. So pl. = 280oC. []D= +87o(C=1, dichloromethane). The analysis is consistent with C29H23ClM4O20,33 H2O.

TLC: S. B; 0,85.

1H-NMR, (M. D.): 2,6 (s, 3H); 2,8 (s, 3H); 3,1 (m, 1H); 3,4 (m, 1H); 3.9 to (K, 1H); with 4.65 (t, 1H); 5,7 (d, 1H); and 7.3 (m, 9H); to 7.95 (s, 1H); and 8.4 (d, 1H); and 9.1 (s, 1H).

IR-spectrum: 3250, 1660, 1600, 1520, 1490, 1440, 1360, 1220, 840, 700 cm-1.

Example 8.H: (4-Oxo-1-phenyl-3,4,6,7-tetrahydro-[1,4]diazepino [6,7,1-hi] indol-3-yl)amide (3R)-4-chloro-7,8-dimethyl-quinoline-3-carboxylic acid

[formula (I); A = 3-(4-chloro-7,8-dimethyl-chinolin)]

Connection receive under option B, described in example 1.B, of the intermediate product (1. b) and 4-chloro-7,8-dimethyl-quinoline-3 - carboxylic acid. Yield = 35%. Solid yellow color. So pl. = 203oC. []D= +88o(C = 1, dichloromethane). The analysis is consistent with C29H23ClN4O20.5 H2O.

TLC: S. B; 0,90.

1H-NMR, (M. D.): 3,1 (m, 1H); 3,3 (m, 1H); 3.9 to (K, 1H); 4,6 (t, 1H); 5,6 (d, 1H); and 7.3 (m, 9H); 8 (d, 1H); 8.3 (l, 1H); and 9.1 (s, 1H).

IR-spectrum: 3250. 1660, 1600, 1515, 1440, 1395. 1360, 1230. 780, 700 cm-1.

Example 9. A: (3R)-2-Methoxy-N-(9-methyl-4-oxo-1-phenyl - 3,4,6,7-tetrahydro-[1,4]diazepino[6,7,1-hi]indol-3-yl)benzamide

[formula (I); A = 2-methoxyphenyl; R = CHoC (decomposition). []Din = +34o(C = 1, dichloromethane). The analysis is consistent with C28H23N3O3.

TLC: S. A9; 0,66.

1H-NMR, (M. D.): 2,35 (s, 3H); 3,1 (m, 1H); to 3.35 (m, 1H); 4 (m, 1H); to 4.1 (s, 3H); with 4.65 (m, 1H); 5,7 (d, 1H); 7-7,5 (m, 10H); of 8.25 (d, 1H); 9,8 (d, 1H exchange.).

IR-spectrum: 3350, 1680, 1650, 1600, 1510, 1490, 1290, 1240, 1160, 1020, 750, 700 cm-1.

Example 9. B: (3R)-N-(9-Methyl-4-oxo-1-phenyl-3,4,6,7 - tetrahydro-[1,4] diazepino[6,7,1-hi] indol-3-yl)isonicotinamide [formula (I); A = 4-pyridyl; R = CH3]

Connection receive under option a of the intermediate product (2.b) and the acid chloride of isonicotinic acid. Yield = 88%. Solid white color. So pl. = 238-240oC. []D+54o(C=1, dichloromethane). The analysis is consistent with C24H20N4O2.

TLC: S. A10; 0,57.

1H-NMR, (M. D.): 2,35 (s, 3H); 3,05 (m, 1H); of 3.25 (m, 1H); 3.9 to (m, 1H); 4,6 (m, 1H); 5 (d, 1H); 7 (s, 1H); 7,2-7,5 (m, 6N); 7.7 (d, 2H); 8,1 (d, 1H exchangeable); and 8.7 (d, 2H).

IR-spectrum: 3700, 1680, 1650, 1520, 1350, 1280, 1230, 1170, 690, 650 cm-1.

Example 9. B: (9-Methyl-4-oxo-1-phenyl-3,4,6,7-tetrahydro- [1,4]diazepino[6,7,1-hi] indol-3-yl)amide (3R)-4,7-dimethyl-pyrazole [5,1-f][1,2,4]triazine - 3-carboxylic acid

[formula (I); A = 3-(4,7-d what about the product (2.b) and 4,7-dimethyl-pyrazole[5,1-e] [1,2,4] triazine-3-carboxylic acid. Yield = 72%. Solid yellow color. So pl. = 130oC. []D+20o(C = 1, dichloromethane). The analysis is consistent with C26H23N7O2.

TLC: S. A4; 0,37.

1H-NMR, (M. D.); 2,3 (s, 3H); 2,5 (s, 3H); 3,2 (s, 3H); 5,6 (d, 1H); 9,8 (d, 1H).

IR-spectrum: 3100, 2950, 1665 cm-1.

Biological activity of derivatives of diazepinone formula (I) or (Ia) is confirmed by the results of the following tests.

Activity against inhibition phosphodiesterase-IV

The ability of compounds of the formula (I) or (Ia) according to the invention to inhibit phosphodiesterase of cyclic nucleotides, in particular phosphodiesterase-IV, evaluated by determining their IR50(concentration required to inhibit 50% of enzyme activity). The obtained value is compared with IR50rolipram, a specific inhibitor of PDE-IV by the ratio IR50rolipram to IR50the test product compared to the same enzyme preparation.

Different types of phosphodiesterase receive, partially purified on a column of diethylaminoethylcellulose, from Guinea-pig trachea and aorta of dogs using the method developed by W. J. Thompson et al., 1979, Advances in Cyclic Nucleotide and the enzymatic activity of different types of PDE, in particular PDE-IV, carried out according to the method, also developed by W. J. Thompson, see link above. To determine IR50the enzymatic activity measured in the presence of inhibitor at concentration range from 0.1 to 100 Microm.

The table illustrates the inhibitory activity against PDE-IV as compared to that of rolipram when using an enzyme preparation obtained from the trachea of the Guinea pig.

Analysis of the results of the above table shows that tested in the experience of the compounds according to the invention inhibit the enzyme PDE-IV trachea of the Guinea pig, as a rule, is more efficient than rolipram, and in some cases they are 2-3 times more efficient than rolipram.

In addition, tests that are implemented on purified PDE different types of trachea of the Guinea pig or the aorta of the dog, show that the magnitude of IR50benefits of using compounds according to the invention, with respect to PDE type III and type I and type V, much higher than those defined for PDE type IV.

These results show high and selective inhibitory activity of the compounds according to the invention in respect of PDE-IV.

Anti-inflammatory and antiallergic actruly eosinophils, induced by antigenic stimulation or by storage in an aerosol PAF, according to the methodology described Lagente V. and others, Br. D. Pharmacol., 112, R (1994).

Introduction compounds according to the examples (1-30 mg/kg orally) significantly reduces the number of eosinophils in broncho-alveolar washing liquid.

Introduction compounds according to the invention also reduces the inflammatory reaction induced by dropping into the trachea of the Guinea pig interleukin-5.

Inhibition of excretion of cytokines

The active compounds according to the invention in the allocation of cytokines by human mononuclear cells determined in vitro according to the method described by Konno S., and others , Eur. J. Pharmacol., 264, 265-268 (1994), and Endo H. and other Int. Arch. Allergy Immunol., 101, 425/430 (1993), interleukins, and according to the method described by J. Semmler, etc., Int. J. Immunopharmac., 15, 409-413 (1993), and Verghese, M. W., and others, J. Pharmacol. Exp. Ther., 272, 1313-1320 (1995)- tumor necrosis factor. The dose interleukin-2, -4, -5 and-tumor necrosis factor carry out imunnofermentativnaya method. Calculate the concentration IR50, inhibitory 50% of the production of the cytokine-stimulated concanavalin a, phytohemagglutinin or lipopolysaccharide.

Under these conditions, compound f is who or equal to 10-5mol/L.

Daily dose of the compounds according to the invention typically ranges from 2 mg to 1 g/kg body weight.

Compounds according to the invention belong to the category of low-toxic substances.

The results of the above tests show anti-inflammatory and/or immunosuppressive activity of the compounds according to the invention. Compounds according to the invention, therefore, especially suitable for the treatment or prevention:

allergic pathologies, and in particular, asthma, atopic dermatitis;

inflammatory pathologies, in particular at the level of the bronchi, but also rheumatoid arthritis, and inflammatory intestinal diseases (hemorrhagic retrocolic and Crohn's disease); including cases where there is an autoimmune component.

The proposed pharmaceutical composition typically contains 0.5 - 60 wt.% the active substance and 40 to 99.5 wt.% pharmaceutically acceptable filler. Get it known methods.

The proposed pharmaceutical composition may be in the form of any conventional galenic preparations. So, for example, tablets may have the following composition:

the active substance of the formula (I) - (1-75 mg

the salt of the carboxymethyl amylum - 8 mg

magnesium stearate 1 mg

The method of obtaining

Mix the active substance, lactose, microcrystalline cellulose and carboximetilkrahmal. To moisten and pelletized by using an aqueous or alcohol solution of polyvinylpyrrolidone with an appropriate concentration. Dried and sorted according to the size of the granulate. Homogeneous mixing with magnesium stearate. Extruding 200 mg per tablet.

1. Derivatives diazepinone General formula I

< / BR>
in which R is hydrogen, lower alkyl or lower alkoxyl;

A - phenyl, thienyl, 4 - to 7-membered heterophilically the residue containing 1-4 nitrogen atom, unsaturated condensed heterocyclic residue with 1 to 5 nitrogen atoms, unsubstituted or substituted by 1-3 groups selected from the group comprising halogen, lower alkyl, lower halogenated, lower alkoxy, acetoxy, amino, tert. -butoxycarbonylamino, cycloalkylcarbonyl and ndimethylacetamide, provided that when R is hydrogen, then: I) a does not imply 2-indolinyl radical; (II) for racemic forms And does not mean a phenyl radical, substituted with halogen; the halogen and amino; halogenoalkanes group or 1 - 3 CNS groups

their racemic forms, their isoki acceptable salt.

2. Derivatives diazepinone formula I under item 1, in which an absolute configuration of the carbon atom in the-position to the carbonyl diazepinones cycle is (R)-configuration.

3. Derivatives diazepinone formula I under item 1 or 2, in which a represents phenyl, pyridyl, thienyl, pyrimidyl, indolyl, hinely, ethanolic, pyrazoloacridine, imidazopyridine and imidazopyrimidines, unsubstituted or substituted by 1-3 groups selected from the group comprising halogen, lower alkyl, lower halogenated, lower alkoxy, acetoxy, amino, tert. -butoxycarbonylamino, cycloalkylcarbonyl and ndimethylacetamide.

4. Derivatives diazepinone formula I according to any one of paragraphs.1-3, in which R means a lower alkyl or lower alkoxyl.

5. Derivatives diazepinone formula I according to any one of paragraphs.1-4, in which R denotes methyl or methoxy group.

6. Derivatives diazepinone formula I on p. 1, representing a compound selected from the group including

a) (3R)-N-(4-oxo-1-phenyl-3,4,6,7-tetrahydro-[1,4] diazepino-[6,7,1-hi] -indol-3-yl)isonicotinamide;

b) (4-oxo-1-phenyl-3,4,6,7-tetrahydro-[1,4] diazepino[6,7,1-hi]-indol-3-yl)amide(3R)-isoquinoline-3-carboxylic acid;

in) (4-oxo-1-phenyl-3,4,6,7-tetrahydro the-4-oxo-1-phenyl-3,4,6,7-tetrahydro-[1,4]diazepino-[6,7,1-hi] indol-3-yl)amide(3R)-isoquinoline-3-carboxylic acid;

d) (3R)-4-chloro-N-(9-methoxy-4-oxo-1-phenyl-3,4,6,7-tetrahydro-[1,4]diazepino[6,7,1-hi]indol-3-yl)benzamide;

(e) (9-methoxy-4-oxo-1-phenyl-3,4,6,7-tetrahydro-[1,4]diazepino[6,7,1-hi] indol-3-yl)amide(3R)-quinoline-3-carboxylic acid;

W) (9-methoxy-4-oxo-1-phenyl-3,4,6,7-tetrahydro-[1,4]diazepino[6,7,1-hi] indol-3-yl)amide(3R)-quinoline-6-carboxylic acid;

C) (3R)-3-chloro-4-methoxy-N-(4-oxo-1-phenyl-3,4,6,7-tetrahydro-[1,4]diazepino[6,7,1-hi]indol-3-yl)benzamide;

and) (3R)-4-amino-3,5-dichloro-N-(4-oxo-1-phenyl-3,4,6,7-tetrahydro-[1,4] diazepino[6,7,1-hi]indol-3-yl)benzamide;

K) (3R)-5,6-dichloro-N-(4-oxo-1-phenyl-3,4,6,7-tetrahydro-[1,4] diazepino[6,7,1-hi]indol-3-yl)nicotinamide;

l) (3R)-2-methoxy-N-(9-methyl-4-oxo-1-phenyl-3,4,6,7-tetrahydro[1,4]diazepino[6,7,1-hi]indol-3-yl)benzamide;

m) (3R)-N-(9-methyl-4-oxo-1-phenyl-3,4,6,7-tetrahydro-[1,4] diazepino[6,7,1-hi]indol-3-yl)isonicotinamide;

n) (9-methyl-4-oxo-1-phenyl-3,4,6,7-tetrahydro-[1,4]diazepino-[6,7,1-hi] indol-3-yl)amide(3R)-4,7-dimethyl-pyrazole-[5,1-c] [1,2,4] triazine-3-carboxylic acid.

7. Derivatives diazepinone General formula II

< / BR>
in which R denotes methyl or methoxy group,

representing intermediate compounds for obtaining derivatives of diazepinone under item 1, in which R is methyl or methoxy.

8. Farowe nitrogen-containing heterocyclic compounds and pharmaceutically acceptable filler, characterized in that as the nitrogen-containing heterocyclic compounds it contains at least one derivative of diazepinone General formula Ia

< / BR>
in which R' is hydrogen, lower alkyl or lower alkoxyl;

A' is phenyl, thienyl, 4 - to 7-membered heterophilically the residue containing 1-4 nitrogen atom, unsaturated condensed heterocyclic residue with 1 to 5 nitrogen atoms, unsubstituted or substituted by 1-3 groups selected from the group comprising halogen, lower alkyl, lower halogenated, lower alkoxy, acetoxy, amino, tert.-butoxycarbonylamino, cycloalkylcarbonyl and ndimethylacetamide,

its racemic form, or isomeric configuration defined by the carbon in position 3 diazepinone-4-about the kernel, or a pharmacologically acceptable salt.

9. The pharmaceutical composition according to p. 8, characterized in that it contains a derivative of diazepinone, whose absolute configuration of the carbon atom in the d-position to the carbonyl diazepinones cycle diazepinone is (R)-configuration.

10. The pharmaceutical composition under item 8 or 9, characterized in that it contains a derivative of diazepinone, in which R' denotes methyl or m is t derived diazepinone, selected from the group including

a) (3R)-N-(4-oxo-1-phenyl-3,4,6,7-tetrahydro-[1,4] diazepino-[6,7,1-hi] indol-3-yl)isonicotinamide;

b) (4-oxo-1-phenyl-3,4,6,7-tetrahydro-[1,4]diazepino[6,7,1-hi]indol-3-yl)amide(3R)isoquinoline-3-carboxylic acid;

in) (4-oxo-1-phenyl-3,4,6,7-tetrahydro-[1,4]diazepino[6,7,1-hi]indol-3-yl)amide(3R)-4,7-dimethyl-pyrazole[5,1-c][1,2,4]-triazine-3-carboxylic acid;

g) (9-methyl-4-oxo-1-phenyl-3,4,6,7-tetrahydro-[1,4]diazepino-[6,7,1-hi] indol-3-yl)amide(3R)-isoquinoline-3-carboxylic acid;

d) (3R)-4-chloro-N-(9-methoxy-4-oxo-1-phenyl-3,4,6,7-tetrahydro-[1,4] diazepino[6,7,1-hi]indol-3-yl)benzamide;

(e) (9-methoxy-4-oxo-1-phenyl-3,4,6,7-tetrahydro-[1,4]diazepino[6,7,1-hi] indol-3-yl)amide(3R)-quinoline-3-carboxylic acid;

W) (9-methoxy-4-oxo-1-phenyl-3,4,6,7-tetrahydro-[1,4]diazepino[6,7,1-hi] indol-3-yl)amide(3R)-quinoline-6-carboxylic acid;

C) (3R)-3-chloro-4-methoxy-N-(4-oxo-1-phenyl-3,4,6,7-tetrahydro-[1,4] diazepino[6,7,1-hi]indol-3-yl)benzamide;

and) (3R)-4-amino-3,5-dichloro-N-(4-oxo-1-phenyl-3,4,6,7-tetrahydro-[1,4]diazepino[6,7,1-hi]indol-3-yl)benzamide;

K) (3R)-5,6-dichloro-N-(4-oxo-1-phenyl-3,4,6,7-tetrahydro-[1,4] diazepino[6,7,1-hi]indol-3-yl)nicotinamide;

l) (3R)-2-methoxy-N-(9-methyl-4-oxo-1-phenyl-3,4,6,7-tetrahydro-[1,4]diazepino[6,7,1-hi]indol-3-yl)benzamide;

m) (3R)-N-(9-methyl-4-oxo-1-phenyl-3,4,6,7-eno-[6,7,1-hi] indol-3-yl)amide(3R)-4,7-dimethyl-pyrazole-[5,1-c] [1,2,4] triazine-3-carboxylic acid.

 

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